CN102892765B - New cyclohexylamine derivatives having [beta]2 adrenergic agonist and m3 muscarinic antagonist activities - Google Patents

New cyclohexylamine derivatives having [beta]2 adrenergic agonist and m3 muscarinic antagonist activities Download PDF

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CN102892765B
CN102892765B CN201180023678.6A CN201180023678A CN102892765B CN 102892765 B CN102892765 B CN 102892765B CN 201180023678 A CN201180023678 A CN 201180023678A CN 102892765 B CN102892765 B CN 102892765B
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CN102892765A (en
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M·帕拉特坤诺斯
席微亚·芳奎那波
卡洛斯·普伊格杜兰
W·鲁默斯阿马多尔
荷西·艾瓜德博世
J·F·凯特厄拉加瓦罗耶斯
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Almirall SA
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Abstract

The present invention relates to novel compounds having [beta]2 adrenergic agonist and M3 muscarinic antagonist dual activity, to pharmaceutical compositions containing them, to the process for their preparation and to their use in respiratory therapies.

Description

There is the cyclohexylamine derivant of the activity of beta 2-adrenergic agonist and M3 muscarine antagonist
Technical field
The present invention relates to the novel compound with beta 2-adrenergic agonist and M3 muscarine antagonist double activity.The invention still further relates to the pharmaceutical composition containing this new compound, the preparation method of this new compound and the application on respiratory therapy thereof.
Background technology
Bronchodilator occupies very important role for the treatment of respiratory disorder such as COPD and asthma etc.Beta-adrenergic agonist and cholinergic muscarinic antagonist are widely used bronchodilators clinically.The beta-adrenergic agonist that current Inhalation in Treating uses comprises fugitive dose (as salbutamol (qid) or terbutaline diisobutyrate (tid)) and sustained release drug (as salmaterol and formoterol (bid)).These medicaments make bronchiectasis by stimulating the adrenoreceptor of airway smooth muscle, reverse bronchoconstriction agent to the reaction of various medium as acetylcholine.The suction muscarine antagonist used at present comprises fugitive ipratropium bromide or oxitropium bromide (qid) and long-acting tiotropium bromide (qd).These medicaments make bronchiectasis by reducing the effect of the vagus nerve cholinomimetic energy of airway smooth muscle.Except improving the function of lung, these medicaments also can make the life better quality and reduce sb.'s illness took a turn for the worse.In clinical literature, there is much research strongly to show, for the treatment of COPD, taking β-2 agonist more effective (such as than taking separately wherein one with the combination of M3 antagonist, van Noord, J.A., etc., Eur.Respir.J., 26,214-222).Also known in the art, the pharmaceutical composition comprising the combination of two kinds of bronchodilators is used in respiratory therapy.Such as, WO2009013244 discloses a kind of pharmaceutical composition, and it contains the salmaterol as beta-adrenergic agonist and the tiotropium bromide as muscarine antagonist.
With regard to the effect in the treatment of COPD and side effect, have and the single molecule of the double activity of muscarine M3 and β2-adrenoreceptor (MABA) is expected to.Compared with the combination of two kinds of compositions, it has relevant advantage in prescription.And it is also easier to other therapeutic agent if imbedibility antiinflammatory co-formulation is to form triple therapeutic combinations.Therefore, be necessary to research and develop novel compound, it has the activity of beta 2 receptor agonist and muscarinic receptor antagonist simultaneously and is suitable for treatment respiratory disorder as asthma and COPD.
Summary of the invention
The invention provides novel compound, it has the activity of beta 2-adrenergic receptor agonists and muscarinic receptor antagonist simultaneously.Therefore, the compound of formula (I) or the derivant of its pharmaceutically acceptable salt or N-oxide or solvate or deuterate are provided:
Wherein:
X and Y all represents hydrogen atom, or,
X is together with Y shape Cheng – CH=CH-,-CH 2-O-Huo – S-, wherein, for-CH 2the situation of-O-, methylene is connected to the carbon atom had in the amino-substituent of X, and oxygen atom is connected to the carbon atom had in the phenyl ring of Y,
R 1with R 2represent hydrogen atom or C independently 1-4alkyl,
R 3represent following formula:
Wherein:
O R arepresent hydrogen atom, hydroxyl, methylol or C 1-4alkyl,
O R bwith R crepresent thienyl, phenyl, benzyl or C independently 4-6cycloalkyl,
O Z represents direct key or oxygen atom, and
O * represents R 3be connected to the attachment point of the remainder of the molecule of formula (I),
A 1with A 2represent C independently 1-6alkylidene, it is optionally by one or more C 1-4alkyl replaces,
L represent direct key ,-O-,-NH (CO)-,-(CO) NH-Huo – NH (CO) O-, wherein, the situation of Dui Yu – NH (CO) O-, nitrogen-atoms is connected to W substituent group, and oxygen atom is connected to A2 substituent group; And
W represents direct key or optionally by the phenylene that one or more substituent group replaces, this substituent group is selected from halogen atom, C 1-4alkyl, C 1-4alkoxyl and cyano group.
The present invention also provides the pharmaceutical composition containing compound of the present invention and pharmaceutically acceptable carrier.The present invention separately provides the compositions containing compound of the present invention and one or more other therapeutic agent and the pharmaceutical composition containing this compositions.
The present invention also provide a kind of be used for treating in mammal with the related disease of double activity of beta 2-adrenergic receptor and M-ChR (such as, pneumonopathy (as asthma or chronic obstructive pulmonary disease), premature labor, glaucoma, nervous system disease, heart disease, inflammation, the urinary disorders as urinary incontinence and the gastroenteropathy as irritable bowel syndrome or spastic colitis) method, the method comprise will the compound administration of the present invention for the treatment of effective dose to mammal.The present invention separately provides a kind of Therapeutic Method, and it comprises the compound of the present invention of drug treatment effective dose and the combination of one or more other therapeutic agents.
In other are different, the present invention also provides preparation process and wherein mentioned intermedium, and described intermedium contributes to preparing compound of the present invention.
The present invention also provides the compound of the present invention for Drug therapy as herein described and compound of the present invention manufacturing the purposes in the preparation or medicament being used for the treatment of the disease relevant to the activity of dual beta 2-adrenergic receptor and M-ChR in mammal or disease (such as, as the pulmonary disease of asthma or chronic obstructive pulmonary disease, premature labor, glaucoma, nervous system disease, heart disease, inflammation, the urinary disorders as urinary incontinence and the gastroenteropathy as irritable bowel syndrome or spastic colitis).
Detailed description of the invention
Unless otherwise stated, when describing compound of the present invention, compositions and method, following term has following meaning.
Term C used herein 1-4alkyl comprises the straight chain group or branched group with 1 to 4 carbon atoms.Example comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl or the tert-butyl group.
Term C used herein 1-6alkylidene comprises the alkyl moieties usually with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.C 1-6the example of alkylene group comprises methylene, vinyl, acrylic, cyclobutenyl, pentenyl and hexenyl etc.Usually be not substituted by the alkylidene optionally replaced or replaced by 1,2 or 3 substituent group that can be identical or different.
Term C used herein 1-4alkoxyl comprise by optionally replace, the straight chain of the moieties all with 1 to 4 carbon atoms or the oxy radical of side chain.C 1-4the example of alkoxyl comprises methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy.Alkoxyl is not usually substituted or is replaced by 1,2 or 3 substituent group that can be identical or different.
Term C used herein 4-6cycloalkyl comprises the saturated carbocyclic monocycle or polycyclic moiety with 4 to 6 carbon atoms, preferably 4 to 5 carbon atoms.Example comprises cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.It is cyclopropyl, cyclobutyl and cyclopenta preferably.
Term halogen atom used herein comprises chlorine atom, fluorine atom, bromine atoms or atomic iodine, normally fluorine atom, chlorine atom or bromine atoms.When term halo is used as prefix, there is equivalent.
Term " treatment effective dose " refers to be enough to treatment is effectively measured when being administered to the patient needing treatment.
Term used herein " treatment " refer to treatment patient in disease or medical condition, it comprises:
A () prevents disease or the generation of medical condition, that is, the prophylactic treatment of patient;
B () improves disease or medical condition, that is, make the disease in patient or medical condition disappear;
C () suppresses disease or medical condition, namely slow down the development of disease in patient or medical condition; Or
D () alleviates the symptom of disease in patient or medical condition.
Wording " disease relevant with the activity of beta 2-adrenergic receptor and M-ChR or disease " comprises known or future now by all morbid state relevant with the activity of beta 2-adrenergic receptor and M-ChR that find and/or disease.This morbid state is including, but not limited to pulmonary disease (as asthma and chronic obstructive pulmonary disease (comprising chronic bronchitis and emphysema)), nervous system disease and heart disease.Also known, beta 2-adrenergic receptor activity has the inflammation (patent application see publication No. to be the international patent application of WO 99/30703 and publication No. be EP1 078 629) about premature labor (being the international patent application of WO 98/09632 see publication No.), glaucoma and some type.
On the other hand, M3 receptor active has about gastrointestinal organ disease, as irritable bowel syndrome (IBS) (such as, see, US5397800), Gl ulcer, spastic colitis (such as, see US 4556653); Urinary organs disease, as urinary incontinence (such as, see J.Med.Chem., 2005,48,6597-6606), pollakiuria; The sinus bradycardia that motion sickness and vagus nerve cause.
Term " pharmaceutically acceptable salt " refers to by the standby salt of the alkali or processed with acid that can be administered to patient (such as mammal).This salt can be prepared from by pharmaceutically acceptable inorganic base or organic base and pharmaceutically acceptable mineral acid or organic acid.
By pharmaceutically acceptable acid the salt that derives comprise acetate, benzene sulfonate, benzoate, camsilate, citrate, esilate, formate, fumarate, Fructus Vitis viniferae hydrochlorate, glutamate, Glu, hydrobromate, hydrogen chlorate, hydrofluoride, lactate, maleate, malate, mandelate, mesylate, mucate, nitrate, pantothenate, phosphate, succinate, sulfate, tartrate, p-toluene fulfonate, that acid pungent (1-hydrogen-oxygen 2-naphthoic acid) salt, naphthalenedisulfonic acid (1, 5-naphthalenedisulfonic acid) salt, triphenyl-acetic acid salt etc.Particularly preferably be the salt derived from formic acid, fumaric acid, hydrobromic acid, hydrochloric acid, Fluohydric acid., acetic acid, sulphuric acid, methanesulfonic acid, that acid pungent, tartaric acid, maleic acid, succinic acid and naphthalenedisulfonic acid.
By pharmaceutically acceptable inorganic base the salt that derives comprise aluminum, ammonium, calcium, copper, ferrum, ferrous iron, lithium, magnesium, manganese, sub-manganese, potassium, sodium, zinc etc.Particularly preferably be ammonium salt, calcium salt, magnesium salt, potassium salt and sodium salt.
By pharmaceutically acceptable inorganic base the salt that derives comprise primary amine, the salt of secondary amine and tertiary amine, described primary amine, tertiary amine and secondary amine comprise the amine be substituted, cyclammonium, naturally occurring amine etc., as arginine, betanin, caffeine, gallbladder alkali, N, N'-hexichol ethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dianol, ethanolamine, ethylenediamine, positive ethylmorphine, positive ethyl piperidine, glucamine, glucamine, histidine, breathe out amine, 2-aminopropane., lysine, methylglucosamine, morpholine, piperazine, piperidines, polyamino resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), trometamol etc.
Term " solvate " refers to the complex or polymer that are formed by one or more solute molecule (i.e. compound of the present invention or its pharmaceutically acceptable salt) and one or more solvent molecule.This solvate normally crystalline solid, it has solute and the solvent of fixed molar ratio example substantially.Such as, typical solvent comprises water, methanol, ethanol, isopropyl alcohol, acetic acid etc.When solvent is water, the solvate formed is hydrate.
Term solvate used herein refers to such compound: the solvent also comprising stoichiometry or non-stoichiometry amount, and as water, acetone, ethanol, methanol, dichloromethane, 2-propanol etc., it combines with non-covalent intermolecular forces.When solvent is water, replace solvate with term hydrate.
Term deuterated derivatives used herein comprises compound of the present invention, wherein, on privileged site, at least one hydrogen atom replace by deuterium.Deuterium (D or 2h) be the stable isotope of hydrogen, it is 0.015 % by mole at occurring in nature content.
Hydrogen deuterium exchange (deuterium is incorporated to) is a kind of chemical reaction, and wherein, covalently bound hydrogen atom is replaced by D-atom.This exchange (being incorporated to) reaction can be all or part of.
Usually, the deuterated derivatives of compound of the present invention has an isotope enrichment factor (ratio between isotopic content and this isotopic natural content, namely, the percentage ratio that the position of in the molecule one given hydrogen is incorporated to by deuterium), for each deuterium on the site of the potential deuterium of specifying be present on compound, be at least 3500 (52.5% deuterium is incorporated to).
One preferred embodiment in, the isotope enrichment factor is at least 5000 (75% deuteriums).In a preferred embodiment, the isotope enrichment factor is at least 6333.3 (95% deuterium is incorporated to).In a most preferred embodiment, the isotope enrichment factor is minimum is 6633.3 (99.5% deuterium is incorporated to).Should be appreciated that the isotope enrichment factor and other deuterium site of each deuterium on the deuterium site that is present in and specifies have nothing to do.
The traditional analysis determination isotope enrichment factor known to a person of ordinary skill in the art can be utilized, comprise mass spectral analysis (MS) and nuclear magnetic resonance, NMR (NMR).
Term " amino protecting group " refers to and is suitable for preventing amino nitrogen place that the protecting group of less desirable reaction occurs.Typical amino protecting group includes but not limited to: formyl; Acyl group, as alkanoyl, such as acetyl group; Alkoxy carbonyl group, as tertbutyloxycarbonyl (Boc); Arylmethoxycarbonyl groups, as carbobenzoxy (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); Arylmethyl, as phenyl (Bn), trityl (Tr) and 1,1-bis--(4-anisyl) methyl; Silicyl, as trimethylsilyl (TMS) and tert-butyl dimethylsilyl (TBS); Etc..
Term " hydroxyl protecting group " refers to the protecting group for preventing from going out to occur at hydroxyl less desirable reaction.Typical hydroxyl protecting group includes but not limited to: alkyl, as methyl, ethyl and the tert-butyl group; Acyl group, as alkanoyl, such as acetyl group; Arylmethyl, as phenyl (Bn), p-anisyl (PMB), 9-fluorene methyl (Fm) and benzhydryl (DPM); Silicyl, as trimethylsilyl (TMS) and tertiary fourth silicyl (TBS); Etc..
Compound of the present invention comprises at least one chiral centre.If exist more than a chiral centre, the present invention includes independent diastereomer and the mixture of diastereomer, wherein, the amount of each diastereomer can be equal, or wherein the amount of one or more diastereomers is more.
Usually, X becomes group-CH=CH-Huo – CH together with Y shape 2-O-.Preferably, X is together with Y shape one-tenth-CH=CH-.
Usually, R 1and R 2represent hydrogen atom or methyl independently; Preferably, R 1represent hydrogen and R 2represent methyl, R 1and R 2the two all represents methyl, or R 1with R 2the two all represents hydrogen atom.
In a particularly preferred embodiment, R 1represent hydrogen atom and R 2represent methyl.
Usually, R 3expression ii) group, wherein, Z is oxygen atom and R abe selected from hydrogen atom, hydroxyl and methyl.
On general, R 3expression i) group, wherein:
R arepresent hydrogen atom, hydroxyl and methyl, preferably R arepresent hydroxyl,
R band R crepresent thienyl, cyclopenta or phenyl independently; Preferably represent thienyl or phenyl; More preferably R band R cthe two all represents thienyl.
Usually, A 1and A 2represent C independently 1-6alkylidene, it is optionally by one or two methyl substituted.
Usually, L Xuan Zi – O-, – NH (CO)-He – NH (CO) O-, wherein ， is when – NH (CO) O-, and nitrogen-atoms is connected to W substituent group, and oxygen atom is connected to A2 substituent group.Preferably, L Xuan Zi – O-Ji – NH (CO)-.
In order to avoid uncertain, the right-hand side being described to the part of possible L group is connected to A2, and the left-hand side of described part is connected to W.
Usually, W represents phenylene, and it is optionally replaced by one or two substituent group being selected from chlorine atom, methyl, methoxyl group and cyano group, and preferably, this phenylene is replaced by the substituent group that two are selected from chlorine atom, methoxyl group and cyano group.In an embodiment of the invention, X is together with Y shape Cheng – CH=CH-Huo – CH 2-O-, R 1represent hydrogen atom or methyl, R 2represent hydrogen atom or methyl, R 3the group of expression (i), wherein, R arepresent hydroxyl, R band R cindependently selected from phenyl, cyclopenta and thienyl, or R 3the group of expression (ii), wherein, R arepresent methyl, Z represents oxygen atom, A 1and A 2represent C independently 1-6alkylidene, it is optionally by one or two methyl substituted, L is selected from direct Jian, – O-, – NH (CO)-Ji – NH (CO) O-, and W represents direct key or phenylene, phenylene is optionally replaced by one or two substituent groups being selected from chlorine atom, fluorine atom, methoxyl group and cyano group.Preferably, X is together with Y shape Cheng – CH=CH-, R 1represent hydrogen atom, R 2represent hydrogen atom or methyl, R 3the group of expression (i), wherein, R arepresent hydroxyl, R band R cthe two is all thienyls, A 1and A 2represent C independently 1-6alkylidene, C 1-6alkylidene is optionally by one or two methyl substituted, L is selected from direct Jian, – O-, – NH (CO)-Ji – NH (CO) O-, W represents direct key or phenylene, and phenylene is optionally replaced by one or two substituent groups being selected from chlorine atom, methoxyl group and cyano group.More preferably, R 2represent hydrogen atom, L is selected from direct Jian, – O-, – NH (CO)-Ji – NH (CO) O-, W and represents phenylene, and this phenylene is replaced by the substituent group that two are selected from chlorine atom, methoxyl group or cyano group.
One preferred embodiment in, X is together with Y shape Cheng – CH=CH-, R 1represent hydrogen atom, R 2represent methyl, R 3the group of expression (i), wherein R arepresent hydroxyl, R band R call thienyls, A 1and A 2represent C independently 1-6alkylidene, this C 1-6alkylidene is optionally by one or two methyl substituted, and L Xuan Zi – O-, – NH (CO)-Ji – NH (CO) O-, W represent phenylene, and this phenylene is replaced by the substituent group that two are selected from chlorine atom, methyl, methoxyl group and cyano group.
Special each compound of the present invention comprises:
Formic acid-trans-4-[(9-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } nonyl) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (2:1);
Formic acid-trans-4-[2-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl) phenoxy group] ethyl } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)) acetate (1:1);
Formic acid-trans-4-[3-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl) phenoxy group] propyl group } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (1:1);
Trans-4-[2-[(6-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } hexyl) oxygen base] ethyl } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate fluohydric acid gas;
Trans-4-[3-[(6-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } hexyl) oxygen base] propyl group } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)-acetate hydrofluoride;
Formic acid-trans-4-[{ 3-[4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenoxy group] propyl group } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (1:1);
Trans-4-[2-[4-([(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl]-amino methyl) phenoxy group] propyl group (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)-acetate hydrofluoride;
Trans-4-[3-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenoxy group] ethyl } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)-acetate hydrofluoride;
Trans-4-((3-(2-chloro-4-(((2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl)-5-anisidino-)-3-oxygen propyl group) (methyl) is amino)-cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride;
Trans-4-((3-(2-chloro-4-(((2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl) phenyl amino)-3-oxygen propyl group) (methyl) is amino) cyclohexyl hydroxyl-(two-2-thienyls) acetate hydrofluoride;
Trans-4-[{ 3-[2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxy phenoxy] propyl group } (methyl) is amino] cyclohexyl hydroxyl-(two-2-thienyls) acetate hydrofluoride;
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl) oxygen base] ethyl }-(methyl) is amino] cyclohexyl hydroxyl-(two-2-thienyls) acetate hydrofluoride;
Trans-4-[(3-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino }-3-oxygen propyl group) (methyl) amino]-1-cyclohexyl hydroxyl-(two-2-thienyls) acetate;
Trans-4-[(3-{ [4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] is amino }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[(4-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxycarbonyl propyl] is amino }-4-oxygen-butyl) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate;
Trans-4-[(3-{ [fluorine-based-4-of 2-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino }-3-oxygen propyl group) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate;
Trans-4-[(3-{ [4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-3-anisyl] is amino }-3-oxygen propyl group) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[(3-{ [2, the fluoro-4-of 5-bis-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] amino-3-oxygen propyl group) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[(3-{ [fluorine-based-4-of 2-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] is amino }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[(3-{ [2-chloro-4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl)-5-anisyl] amino-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[3-[2-chloro-4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl)-5-methoxy phenoxy] propyl group } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[{ 2-[({ [2-cyano group-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl)-oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[{ 2-[({ [2, the fluoro-4-of 5-bis-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] amino carbonyl) oxygen base] ethyl-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[(3-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-5-anisyl] amino-2,2-dimethyl-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate;
Trans-4-[{ 4-[2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxy phenoxy] butyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(5-hydroxyl-3-oxo-3,4-dihydro base-2H-1,4-benzoxazine-8-base) ethyl] amino methyl)-5-anisyl] amino carbonyl) oxygen]-ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate;
Trans-4-[(9-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl]-amino } nonyl) (methyl) amino] cyclohexyl 9-methyl-9H-xanthene-9-carboxylate;
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl) oxygen] ethyl } (methyl)-amino] cyclohexyl (2R)-cyclopenta (hydroxyl) phenyl acetate; And
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl) oxygen base] ethyl } (methyl) is amino] cyclohexyl (2S)-cyclopenta (hydroxyl) 2-thiophene acetate.
The compound of particular importance is:
Formic acid-trans-4-[(9-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } nonyl) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (2:1);
Formic acid-trans-4-[3-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl) phenoxy group] propyl group } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (1:1);
Trans-4-[3-[(6-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } hexyl) oxygen base] propyl group } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)-acetate hydrofluoride;
Formic acid-trans-4-[{ 3-[4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenoxy group] propyl group } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (1:1);
Trans-4-((3-(2-chloro-4-(((2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl)-5-anisidino-)-3-oxygen propyl group) (methyl) is amino)-cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride;
Trans-4-[{ 3-[2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxy phenoxy] propyl group } (methyl) is amino] cyclohexyl hydroxyl-(two-2-thienyls) acetate hydrofluoride;
Trans-4-[(3-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino }-3-oxygen propyl group) (methyl) amino]-1-cyclohexyl hydroxyl-(two-2-thienyls) acetate;
Trans-4-[(4-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxycarbonyl propyl] is amino }-4-oxygen-butyl) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate;
Trans-4-[(3-{ [fluorine-based-4-of 2-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino }-3-oxygen propyl group) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate;
Trans-4-[(3-{ [2-chloro-4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl)-5-anisyl] amino-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[3-[2-chloro-4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl)-5-methoxy phenoxy] propyl group } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[{ 2-[({ [2-cyano group-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl)-oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[{ 4-[2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxy phenoxy] butyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2);
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(5-hydroxyl-3-oxo-3,4-dihydro base-2H-1,4-benzoxazine-8-base) ethyl] amino methyl)-5-anisyl] amino carbonyl) oxygen]-ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate; And
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl) oxygen] ethyl } (methyl)-amino] cyclohexyl (2R)-cyclopenta (hydroxyl) phenyl acetate.
In embodiments of the present invention, pharmaceutical composition also comprises one or more other therapeutic agents for the treatment of effective dose, and especially one or more are selected from the medicine of corticosteroid and PDE4 inhibitor.
In another embodiment of the invention, pharmaceutical composition is formulated into by sucking administration.
As elucidated before compound of the present invention also can with one or more combination with other therapeutic agents, be particularly selected from the pharmaceutical agent combinations of corticosteroid and PDE4 inhibitor with one or more.
The present invention is also for the compound of formula (I), and it for using in the treatment pathologic conditions relevant with the activity of both beta 2-adrenergic receptor and M-ChR or disease (such as pulmonary disease).Pulmonary disease is asthma or chronic obstructive pulmonary disease particularly.
The pathologic conditions can treated in scope of the present invention or disease comprise and are selected from premature labor, glaucoma, nervous system disease, heart disease, the disease of the urinary tract disease of inflammation, such as urinary incontinence and the gastrointestinal disease of such as irritable bowel syndrome or spastic colitis or disease.
The present invention also for formula (I) compound for the manufacture of be used for treating the pathologic conditions relevant with a kind of or the beta 2-adrenergic receptor of two kinds and M-ChR activity or disease (as pulmonary disease, especially asthma or chronic obstructive pulmonary disease; Premature labor; Glaucoma; Nervous system disease; Heart disease; Inflammation; Urinary tract disease and gastroenteropathy) the purposes of medicament.
The present invention is also for the method for these diseases for the treatment of, and what the method comprised drug treatment effective dose comprises dual beta 2-adrenergic receptor agonists and the pharmaceutical composition of muscarinic receptor antagonist according to of the present invention.The method also comprises one or more other the therapeutic agent being selected from corticosteroid and PDE4 inhibitor of drug treatment effective dose.
The present invention is also for the method for activity regulating beta 2-adrenergic receptor and/or M3 receptor, and the method comprises with the compound of the formula of regulated quantity (I) to stimulate beta 2-adrenergic receptor and/or to block M3 receptor.
Overall synthesis step
Compound of the present invention can utilize method as herein described and step or utilize similar method and step to prepare.It should be understood that wherein, provide common or preferred process condition (that is, the mol ratio, solvent, pressure etc. of reaction temperature, time, reactant); Also other process condition can be used, except being otherwise noted.Best reaction condition can according to specific reactant used, solvent and changing, but this condition measures according to routine optimization step by one of skill in the art.
In addition, those skilled in the art should know, need traditional protecting group to experience less desirable reaction to prevent some functional group.Suitable protecting group is selected and for protection with go protection to be known in field to select appropraite condition for specific functional group.Such as; be described in the list of references that many protecting groups and their introducing and removing is mentioned in Publication about Document and the document: T.W.Greene and G.M.Wuts; Protecting Groups in Organic Synthesis; Third Edition; Wiley; New York, 1999.
The preparation process of compound of the present invention provides as other embodiments of the present invention and by step explanation below.
The approach of the most convenient of the compound of preparation formula (I) just like described in scheme 1.
scheme 1
The compound of formula (I) reacts by the intermedium of formula (II) and the intermedium of formula (III) and is prepared into, wherein, and X 1represent and depart from base, such as halogen atom or active ester (as mesylate or toluene fulfonate), P 1and P 3represent hydrogen atom or oxygen protecting group (as silicyl or benzyl ether) independently, P 2represent hydrogen atom or nitrogen-protecting group (as benzyl).In aprotic polar solvent (such as DMF, 1-Methyl-2-Pyrrolidone or DMSO), in the temperature range between room temperature and 200 DEG C, and under sour remover (as sodium bicarbonate or tertiary amine) exists, this reaction is carried out best.
Or the compound of formula (I) can be reacted by the intermedium of formula V and the intermedium of formula (VI) and is prepared into, wherein, X 1, P 1and P 3meaning described above, synthesis program is same as recited above, subsequently, removes the protecting group be present in intermedium, obtains the compound of formula (I).Such as, this protection process of going comprises desilylation process, and this realizes by being used in the temperature range between 0 DEG C and 50 DEG C, by triethylamine three hydrofluoride, TBAF, hydrogen chloride or other acid reagent etc. in the atent solvent as THF.Go protection also can be undertaken by debenzylation procedure, such as, this passes through in atent solvent (as ethanol or THF) or solvent mixture, makes hydrogenation of compounds to realize under the existence of catalyst (as charcoal palladium catalyst).Carry out in the temperature range of this reaction usually under 10 hydrogen pressures to 60psi and between room temperature and 50 DEG C.
In another diverse ways, the compound of formula (I) also the intermedium of through type (IV) and the intermedium of formula (III) can react and make, wherein, and A 0the group represented can provide A with the adjacent methylene newly formed 1group, it is R 0hydrogen or C 1-4alkyl.In the solvent or solvent mixture of such as THF, methanol, dichloromethane or DMSO, under the reaction temperature between 0 ° and 60 DEG C, and utilize hydride (as sodium borohydride or triacetyl oxygen boron hydride) to be used as reducing agent, this reaction is carried out best.
The compound of formula (II) can utilize known steps to be made up, as described in scheme 2 of the starting material that can have commercially bought and reagent.
scheme 2
The intermedium of formula (II) can be made up through acylation with sulfuryl halide under the existence of acid scavenger of the ethanol derivant of formula (VII), or makes through halogenation from various different halide reagent.
The intermedium of formula (VII) by amine and the corresponding alkanisation part (IXa) of formula (VIII) direct alkanisation and making under the existence of the acid scavenger of such as tertiary amine, wherein, X 3represent and depart from base, such as halogen atom or active ester (such as mesylate or toluene fulfonate).
Or the intermedium of formula (II) can directly be obtained by the intermedium of formula (VIII) and intermedium (IXb), wherein, X 1and X 3as previously mentioned.
The amino ester derivative of formula (VIII) is made by the compound of formula (X) being gone protection, wherein, and P 4representing protecting group, such as, realizing by removing tertbutyloxycarbonyl (BOC) under the condition that there is the acidic intermedium of such as hydrogen chloride in THF.
The intermedium of formula (X) is prepared by following best: the amino alcohol derivative known by the document of formula (XII) and the methyl ester derivative of formula (XI), under the alkali of such as sodium chloride exists, transesterification process occurs, and by distillation (such as toluene), balance is shifted.
The intermedium of formula (III) to be extensively described in document (such as, example 6, the intermedium 65 of WO2008149110, the example 3B of US2007249674 see US2004242622), and can prepare according to the identical synthesis step described in it.
The intermedium of formula (IV) is prepared by following steps: the intermedium utilizing the oxidizing formula (XIII) of such as manganese dioxide or Dess-Martin reagent, or, under acid scavenger exists, use the alkylating agent of formula (XIV) by the direct alkanisation of intermedium of formula (VIII).Compound (IV) also obtains by following methods: acetaldehyde (XVIII) and methoxyl methyl triphenyl phasphine reacted under the alkali of such as lithium two (trimethylsilyl) aminate exists and make intermedium enol ether generation acidic hydrolysis subsequently, or obtained by the oxidation of ethenyl derivatives (XX), ethenyl derivatives (XX) can utilize the alkylation reaction of (VIII) and intermedium (XIX) and obtain.This oxidation can utilize various different reagent to carry out, such as, tetrahydro osmium under N-methylmorphine N-oxide exists.
scheme 3
The intermedium of formula (V) can be prepared by specifically going protection step, such as, by the acid medium process N-BOC derivant of such as hydrogen chloride in THF by the homoplasmon of their N-protected (XV).
scheme 4
The intermedium of formula (XV) can be utilized step known in the art to prepare by the intermedium of formula (VIII), such as, under the existence of acid scavenger (such as triamine), with the intermedium generation alkanisation of formula (XVI), or with the intermedium generation alkanisation of formula (XVII), wherein, A 3add that other 3 adjacent carbon atoms can obtain A 2.
Example
Summary.Reagent, initial substance and solvent can be bought from supplier and use.Concentrated referring to utilizes B ü chi spin vaporizer to vaporize under vacuo.When needing, analysed by the anxious poly layer of silica gel (40-63 μm) with shown dicyandiamide solution, or utilize the HPLC condition (the following descriptions see used two systems) of preparation, purification reaction product.Spectroscopic data record is on Varian Gemini 300 spectrogrph.HPLC-MS is performed in Gilson instrument, and Gilson apparatus preparation forms pump, Gilson170 diode arrays detector and Thermoquest Finnigan aQa detector by Gilson piston pump 321, Gilson 864 vacuum degasifer, Gilson liquid processor 215, Gilson 189 injection unit, Gilson Valvemate 7000,1/1000 separator, Gilson307.
HPLC system 1:
C-18 reversed-phase column Silicon stone is from MERCK, and water/acetonitrile, as cleaning mixture [0.1%v/v ammonium formates buffering], uses the gradient of 0% to 100%.
HPLC system 2:
C-18 reversed-phase column Silicon stone is from MERCK, and water/acetonitrile (not having buffer agent), as cleaning mixture, uses the gradient of 0% to 100%.
Intermedium 1:
The tert-butyl group (trans-4-hydroxy-cyclohexyl) carbamate
Di-t-butyl two carbonate (31.2g, 0.14mol) is added in the solution of (1R, 4R)-4-aminocyclohexanol (15g, 0.13mol) in acetonitrile (240mL).This mixture at room temperature stirs whole evening.Gained precipitate hexane/ethyl salt (3:1) and hexane rinse, and can obtain the title compound (83%) of white solid.
1H NMR(300MHz,CHLOROFORM-d)ppm 1.17(br.s.,2H)1.44(br.s.,9H)1.32-1.40(m,2H)1.99(br.s.,4H)3.44(br.s.,1H)3.61(br.s.,1H)4.38(br.s.,1H)
Intermedium 2:
Trans-4-(methylamino) Hexalin
The tert-butyl group (trans-4-hydroxy-cyclohexyl) carbaminate (intermedium 1,10g, 0.046mol) is slowly added in the mixture of Li-Al hydrogen compound (9g, 0.23mol) in oxolane (425mL).When this mixture cool to room temperature, then the 4N NaOH solution of the water of 9ml, 9ml and the water of 18ml are instilled carefully in succession.Under reduced pressure remove organic solvent, gained coarse fodder dissolves with chloroform again, and dry over magnesium sulfate, then evaporation of filtrate is with drying, and evaporates simultaneously with hexane, then obtain the title compound of white solid.This intermedium is also described in JMC, and 1987,30 (2), p313.
1H NMR(300MHz,CHLOROFORM-d)ppm 1.04-1.20(m,2H)1.25-1.40(m,2H)1.97(br.s.,4H)2.27-2.40(m,1H)3.57-3.70(m,1H)
Intermedium 3:
Tert-butyl (trans-4-hydroxy-cyclohexyl) methylamino formates
Two-tert-butyl two carbonate (9.9g, 0.04mol) is added to trans-4-(methylamino) Hexalin (intermedium 2,5.3g, the 0.04mol) solution in acetonitrile (92mL).Afterwards, mixture is at room temperature stirred whole evening.Under reduced pressure remove solvent, carry out column chromatography by silica gel, wash with the mixture of chloroform/methanol (from 75:1 to 4:1), in addition purification coarse fodder and obtain the title compound (87%) of colorless oil.
1H NMR(300MHz,CHLOROFORM-d).ppm 1.34-1.43(m,2H)1.46(s,9H)1.49-1.57(m,2H)1.70(d,J＝9.89Hz,2H)2.03(br.s.,3H)2.71(br.s.,3H)3.57(br.s.,1H)
Intermedium 4:
Trans-4-[(uncle-butoxy carbonyl) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls)-acetate
First by tert-butyl (trans-4-hydroxy-cyclohexyl)-methylamino formic acid esters (intermedium 3; 6g, solution 0.02mol) in dry toluene (95mL), secondly by sodium hydride (60%, 0.45g, 0.01mol) add in the solution of methylhydroxy (two-2-thienyls) acetate (5.8g, 0.02mol) (its preparation can be described according to Acta Chemica Scandinavica 24 (1970) 1590-1596) in dry toluene (95mL).After a few minutes, mixture is warmed to 155 DEG C, and solvent is distilled and simultaneously replaced.This step carries out 1 half hour.By mixture cool to room temperature also with ether (300mL) dilution.Organic layer is with sodium bicarbonate 4% (2x 200mL) and normal saline washing, drying, filtration, under reduced pressure vaporize, and obtaining the title compound (69%) of yellow solid (69%), it does not need be further purified and be used to next step.
LRMS(m/z):452(M+1) +.
Intermedium 5
Trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate
Hydrogen chloride 4M in dioxanes (27mL) is added to trans-4-[(uncle-butoxy carbonyl) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 4; 8.1g, 0.01mol) in solution in dioxanes (13.5mL).Mixture was in stirred at ambient temperature 24 hours.Gained precipitate is filtered and uses washed with ether.By soluble in water for gained coarse fodder, and add potassium carbonate until pH=8-9.Quench by ethyl acetate and get product, and use normal saline washing organic layer, in addition dry, be evaporated to dry and obtain the title compound (78%) of white solid.
LRMS(m/z):352(M+1) +.
1H NMR(300MHz,CHLOROFORM-d)ppm 1.14-1.30(m,2H)1.42-1.57(m,2H)1.88-2.11(m,4H)2.36-2.48(m,1H)3.71(s,3H)4.82-4.95(m,1H)6.94-7.00(m,2H)7.14-7.19(m,2H)7.25-7.30(m,2H)
Intermedium 6:
Trans-4-[(9-bromine nonyl) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.5g, 0.001mol), 1,9-bis-bromononane (2.9mL, 0.01mol) and triethylamine (0.44mL, 0.003mol) mix under a hydrogen atmosphere, and stir 94 hours at 70 DEG C.Evaporation reaction mixture also carries out column chromatography with silica gel, with chloroform/methanol (by 100to 4:1) washing, thus purification, obtain the title compound (55%) of brown oil.
LRMS(m/z):556,558(1Br)(M,M+2) +
Intermedium 7:
Trans-4-[(9-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino nonyl) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By the trans-4-in dimethyl acetylamide (9mL) [(9-bromine nonyl) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 6; 0.44g, 0.79mmol), 5-((1R)-2-amino-1-{ [tert-butyl (dimethyl)-silicyl] oxygen base } ethyl)-8-hydrogen-oxygen quinoline-2 (1H)-one (its preparation can according to the preparation 8 of US20060035931) (0.26g, 0.79mmol) and the mixture of sodium bicarbonate (0.08g, 0.95mmol) at 60 DEG C, stir whole evening.Under reduced pressure remove organic solvent, coarse fodder is separated between ethyl acetate and water.By organic layers with water and normal saline washing, drying, filtration and evaporation, gained coarse fodder silica gel carries out column chromatography, and with chloroform/methanol (by 15:1 to 4:1) washing, thus purification obtains the title compound (25%) of yellow oily.
LRMS(m/z):811(M+1) +
Example 1
Trans-4-[(9-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl]-amino } nonyl) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate formates (2:1)
By triethylamine three hydrofluoride (0.14mL, 0.89mmol) be added to trans-4-[(9-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] saddle base } nonyl) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 7 under nitrogen atmosphere; 0.8g, 0.13mmol) solution in oxolane (5.1mL).Reactant mixture was in stirred at ambient temperature 20 hours, and reaction coarse fodder methene chloride dilutes, by the in addition rinsing, drying of organic layer sodium bicarbonate and saline, filtration and evaporation.Generate coarse fodder pre-prepared reversed-phase HPLC (system 1) in addition purification, and obtain the title compound (61%) of colorless solid.
LRMS(m/z):696(M+1) +.
1H NMR(400MHz, )ppm 1.24(s,10H)1.36(br.s.,6H)1.53(br.s.,4H)1.71(br.s.,2H)1.92(br.s.,2H)2.14(s,3H)2.31-2.46(m,4H)2.69-2.80(m,2H)2.81-2.94(m,2H)5.23(dd,J＝8.79,3.71Hz,1H)6.51(d,J＝10.16Hz,1H)6.95-7.00(m,3H)7.07(dd,J＝3.71,1.37Hz,2H)7.09(d,J＝8.21Hz,1H)7.46(dd,J＝5.08,1.17Hz,2H)8.19(d,J＝9.77Hz,1H)8.39(br.s.,2H,x2HCOOH)
Intermedium 8.2-[4-(2-bromine oxethyl) phenyl] ethanol
Glycol dibromide (15.6mL, 1.3mol) and potassium carbonate (13g, 0.09mol) are added to the solution of 4-(2-hydrogen-oxygen ethyl) phenol (5g, 0.035mol) in acetone (50mL).Mixture stirs 48 hours at 80 DEG C.Salt is filtered, and mixture is evaporated.Gained coarse fodder is separated between ethyl acetate/water.By organic layer sodium hydroxide 2N, water and normal saline washing, drying, filtration, and under reduced pressure removed by solvent, and obtain the title compound (73%) of white solid, it does not need be further purified and be used to lower step.
LRMS(m/z):246(M+1) +
Intermedium 9
Trans-4-[{ 2-[4-(2-ethoxy) phenoxy group] ethyl } (methyl) is amino] cyclohexyl hydroxyl-(two-2-thienyls) acetate
By trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.35g, 0.001mol), 2-[4-(2-bromine oxethyl) phenyl] ethanol (intermedium 8; 0.36g, 0.0015mol) and triethylamine (0.27mL, 0.002mol) according to the experimental procedure of intermedium 6, and carry out column chromatography with silica gel, with chloroform/methanol (by 75:1 to 25:1) washing, and obtain the title compound (57%) of yellow oily.
LRMS(m/z):516(M+1) +.
Intermedium 10
Trans-4-{ methyl [2-(4-{2-[(methyl sulphonyl) oxygen base] ethyl } phenoxy group) ethyl] amino-cyclohexyl hydroxyl (two-2-thienyls) acetate
By methane sulfonyl chloride (0.03mL, 0.5mmol) at 0 DEG C, join trans-4-[{ 2-[4-(2-ethoxy) phenoxy group } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 9 in 15 minutes; 0.22g, 0.44mmol) mixture in chloroform (3mL), then in stirred at ambient temperature 24 hours.Afterwards, with chloroform dilution, and with sodium bicarbonate 4%, water and normal saline washing, drying and filtration.Under reduced pressure by removal of solvents, gained coarse fodder silica gel carries out column chromatography, with chloroform/methanol 50:1 washing, thus purification and obtain the title compound (70%) of yellow oily.
LRMS(m/z):594(M+1) +
Intermedium 11
Trans-4-[2-[4-(2-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino ethyl) phenyl] ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
Amino by trans-4-{ methyl [2-(4-{2-[(methyl sulphonyl) oxygen base] ethyl }-phenoxy group) ethyl] } cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 10; 0.16g, 0.27mmol), 5-((1R)-2-amino-1-{ [tert-butyl (dimethyl) silicyl] oxygen base } ethyl)-8-oxyquinoline-2 (1H)-one (prepared by the preparation 8 according to US20060035931) (0.09g, 0.27mmol) and sodium bicarbonate (0.03g, 0.33mmol) prepare the title compound (33%) of brown oil according to the experimental procedure of intermedium 7, gained coarse fodder does not need to be further purified and for next step.
LRMS(m/z):833(M+1) +.
Example 2
Trans-4-[2-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl) phenoxy group] ethyl } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate formates (1:1)
By trans-4-[2-[4-(2-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl]-oxygen base }-2-(8-hydroxyl-2-oxo-1, 2-dihydroquinoline-5-base) ethyl] amino ethyl) phenoxy group] ethyl-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 11, 0.25g, 0.09mmol) and triethylamine three hydrofluoride (0.25mL, 1.53mmol) according to the experimental procedure described in example 1, again with prepare reversed-phase HPLC (system 1) in addition purification and the title compound (25%) of white solid.
LRMS(m/z):717(M+1) +.
Intermedium 12
Trans-4-[{ 3-[4-(2-ethoxy) phenoxy group] propyl group } (methyl) is amino] cyclohexyl-hydroxy (two-2-thienyls) acetate
By 2-(4-(3-bromine propoxyl group) phenyl) ethanol (prepared by the intermedium 26 according to WO20080961275) (1.1g, 0.004mol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 1g, 0.003mol) and triethylamine (0.78mL, 0.005mol), prepared by the experimental procedure according to intermedium 6, recycle silicon glue carries out column chromatography, washs thus purification with chloroform/methanol 15:1, obtains the title compound (41%) of colorless oil.
LRMS(m/z):530(M+1) +.
Intermedium 13
Trans-4-{ methyl [3-(4-{2-[(methyl sulphonyl) oxygen base] ethyl } phenoxy group) propyl group] amino-cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[4-(2-ethoxy) benzene oxygen] propyl group }-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 12; 0.63g; 0.001mol), triethylamine (0.14mL; 0.001mol) and methane sulfonyl chloride (0.1mL; 0.001mol) prepare according to the experimental procedure (response time: 3 hours) described in intermedium 10; recycle silicon glue carries out column chromatography, washs thus purification with chloroform/methanol (by 50:1 to 15:1), and obtains the title compound (83%) of colorless oil.
LRMS(m/z):608(M+1) +.
Intermedium 14
Trans-4-[3-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl) phenoxy group] propyl group } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
Amino by trans-4-{ methyl [3-(4-{2-[(methyl sulphonyl) oxygen base] ethyl }-phenoxy group) propyl group] } cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 13; 0.6g, 0.9mmol), 5-((1R)-2-amino-1-{ [tert-butyl (dimethyl) silicyl] oxygen base } ethyl)-8-oxyquinoline-2 (1H)-one (prepared by the preparation 8 according to US20060035931) (0.3g, 0.9mmol) and sodium bicarbonate (0.1g, 1.2mmol) prepare the title compound (25%) of brown oil according to the experimental procedure (response time: 32 hours) described in intermedium 7.Gained coarse fodder does not need to be further purified and for lower step.
LRMS(m/z):847(M+1) +.
Example 3
Trans-4-[3-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl) phenoxy group] propyl group } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate formates (1:1).
By trans-4-[{ 3-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino } ethyl) phenoxy group] propyl group } (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 14; 0.87g, 0.25mmol) and triethylamine three hydrofluoride (0.84mL, 5.19mmol) prepare according to the experimental procedure described in example 1, again with preparing reversed-phase HPLC (system 1) and lyophilization purification in addition, and obtain the title compound (27%) of white solid.
LRMS(m/z):742(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.29(br.s.,4H)1.64(br.s.,2H)1.72(br.s.,2H)1.85(br.s.,2H)2.09(s,3H)2.11(br.s.,2H)2.33(br.s.,1H)2.63(br.s.,2H)2.73(br.s.,3H)3.86(br.s.,2H)4.62(br.s.,2H)5.02(br.s.,1H)6.44(d,J＝9.89Hz,1H)6.76(br.s.,3H)6.83-6.95(m,3H)6.95-7.07(m,4H)7.40(br.s.,2H)8.09(d,J＝9.89Hz,1H)8.26(s,1H,HCOOH)
Intermedium 15
13,13,14,14-tetramethyl-1-phenyl-2,5,12-trioxa-13-silicon pentadecane.
By sodium hydride (32%p/v, 9.6mL, 0.07mol) instill 2-(phenoxy group) ethanol (1.8mL, 0.01mol), (6-bromine hexyloxy) (tert-butyl) dimethylamino silane (7.18mL, 0.02mol) and in the mixture of TBuA bromide (0.23g, 0.71mmol).This mixture vigorous stirring whole evening at 70 DEG C.Water (200mL) is added in mixture, quenches get coarse fodder with hexane (2x 100mL), in conjunction with organic layers with water and normal saline washing, drying, filter and be evaporated to dry.Recycle silicon glue carries out column chromatography, with the washing of hexane/ethyl salt (from 50:1 to 5:1), thus by the coarse fodder grease that obtains in addition purification, obtains the title compound (85%) of colorless oil.
LRMS(m/z):367(M+1) +.
Intermedium 16
2-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] ethanol
Charcoal palladium catalyst (10%, 0.3g) is joined 13,13,14,14-tetramethyl-1-phenyl-2,5,12-trioxa-13-silicon pentadecane (intermedium 15; 3.1g, 0.008mol) in the solution of methanol (74mL).Mixture under a hydrogen atmosphere (balloon pressure) stirring at room temperature whole evening.Filtration catalizer, vapourisation under reduced pressure filtrate, obtains coarse fodder, and recycle silicon glue carries out column chromatography, with hexane/ethyl salt (by 9:1 to 4:1) washing, thus purification coarse fodder, and obtain the title compound (77%) of colorless oil.
1H NMR(300MHz,CHLOROFORM-d).ppm 0.02(s,3H)0.85(s,9H)1.31(ddd,J＝7.35,3.98,3.78Hz,4H)1.42-1.57(m,2H)1.97(t,J＝6.18Hz,2H)3.43(t,J＝6.59Hz,2H)3.46-3.51(m,2H)3.56(t,J＝6.45Hz,2H)3.68(dt,J＝5.84,4.64Hz,2H)
Intermedium 17
2-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] ethyl methane mesylate
By 2-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl)-oxygen base] ethyl (intermedium 16; 2g; 0.007mol), triethylamine (3.52mL; 0.02mol) and methane sulfonyl chloride (1.2mL; 0.01mol); prepare according to the experimental procedure described in intermedium 10; recycle silicon glue carries out column chromatography, washs thus purification by hexane/ethyl acetate (by 5:1 to 3:1), obtains the title compound (92%) of colorless oil.
1H NMR(300MHz,CHLOROFORM-d).ppm 0.05(s,6H)0.89(s,9H)1.30-1.42(m,4H)1.58(br.s.,4H)3.06(s,3H)3.48(t,J＝6.59Hz,2H)3.60(t,J＝6.45Hz,2H)3.69(d,J＝4.67Hz,2H)4.37(d,J＝4.39Hz,2H)
Intermedium 18
Trans-4-[2-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] ethyl }-(methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
By 2-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] ethyl methane mesylate (intermedium 17; 0.45g, 1.28mmol), trans-4-(methylamino)-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5,0.3g, 0.85mmol) and triethylamine (0.2mL, 1.71mmol), prepare according to the experimental procedure described in intermedium 6, recycle silicon glue carries out column chromatography, washs thus purification by chloroform/methanol (by 50/1 to 25/1), obtains the title compound (31%) of oily.
LRMS(m/z):610(M+1) +
Intermedium 19
Trans-4-[{ 2-[(6-ethoxy) oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
Hydrochloric acid (1M, 1.13mL) is joined trans-4-[{ 2-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] ethyl } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 18; 0.1g, 0.28mmol) in the solution of oxolane (2.4mL).This mixture was in stirred at ambient temperature 1 hour.Neutralize with the saturated solution of sodium bicarbonate again, quench by ethyl acetate and get coarse fodder, and in addition dry, filter and be evaporated to dry.Gained title compound is colorless oil (85%).
LRMS(m/z):496(M+1) +.
Intermedium 20
Trans-4-{ methyl [2-({ 6-[(mesyl) oxygen base] hexyl } oxygen base) ethyl] is amino } cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 2-[(6-hydroxyl hexyl) oxygen base] ethyl } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 19; 0.1g; 0.31mmol), triethylamine (0.09mL; 0.64mmol) and methane sulfonyl chloride (0.042mL; 0.54mmol); prepare according to the rapid sequence of solid step described in intermedium 10; recycle silicon glue carries out column chromatography, washs by chloroform/methanol (by 50:1 to 25:1), thus purification, obtain the title compound (88%) of oily.
LRMS(m/z):574(M+1) +.
Intermedium 21
Trans-4-[[(12R)-12-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base)-14,14,15,15-tetramethyl-3,13-dioxa-10-azepine-14-silicon 16 alkyl-1-base] (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
Amino by trans-4-{ methyl [2-({ 6-[(methyl sulphonyl) oxygen base] hexyl }-oxygen base) ethyl] } cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 20; 0.16g, 0.28mmol), 5-((1R)-2-amino-1-{ [tert-butyl (dimethyl) silicyl] oxygen base } ethyl)-8-hydrogen-oxygen quinoline-2 (1H)-one (prepared by the preparation 8 according to US20060035931) (0.09g, 0.28mmol) and sodium bicarbonate (0.029g, 0.35mmol) prepare the title compound (16%) of brown oil according to the experimental procedure described in intermedium 7, gained coarse fodder does not need to be further purified and for next step.
LRMS(m/z):811(M+1) +.
Example 4
Trans-4-[2-[(6-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base)-ethyl] is amino } hexyl) oxygen base] ethyl } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)-acetate hydrofluoride
By trans-4-[[(12R)-12-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base)-14,14,15,15-tetramethyl-3,13-dioxa-10-azepine-14-silicon 16 alkyl-1-base] (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 20; 0.24g, 0.05mmol) and triethylamine three hydrofluoride (0.25mL, 1.53mmol) prepare according to the program described in example 1, then with the reversed-phase HPLC (system 2) of preparation and lyophilisation in addition purification and obtain the title compound (39%) of white solid.
LRMS(m/z):699(M+1) +.
Intermedium 22
14,14,15, phytanetriol-phenyl-2,6,13-trioxa-14-silicon 16 alkane
By 3-(phenoxy group) propane-1-alcohol (2mL, 0.01mol), (6-bromine hexyloxy) (tert-butyl) dimethylsilane (7.1mL, 0.02mol), TBuA bromide (0.24g, 0.0007mol) and sodium hydroxide (32%p/v, 9.5mL) prepare according to the experimental procedure described in intermedium 15, recycle silicon glue carries out column chromatography, washs thus purification by hexane/ethyl acetate, obtains the title compound (67%) of colorless oil.
LRMS(m/z):381(M+1) +.
Intermedium 23
3-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] propyl group-1-alcohol
By 14,14,15, phytanetriol-phenyl-2,6,13-trioxa-14-silicon 16 alkane (intermedium 22; 3.3g, 0.008mol) with charcoal palladium (10%, 0.3g) prepare according to the experimental procedure described in intermedium 16, recycle silicon glue carries out column chromatography, washs thus purification by hexane/ethyl acetate 7/1, and obtains the title compound (95%) of colorless oil.
1H NMR(300MHz,CHLOROFORM-d)ppm 0.01(s,6H)0.85(s,9H)1.26-1.35(m,4H)1.42-1.59(m,4H)1.80(d,J＝5.49Hz,2H)3.38(t,J＝6.59Hz,2H)3.52-3.61(m,4H)3.69-3.78(m,2H)
Intermedium 24
3-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] propylmethanediyl sulfonate
By 3-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] propyl group-1-alcohol (intermedium 23; 1g; 0.003mol), triethylamine (1.7mL; 0.01mmol) and methane sulfonyl chloride (0.29mL; 0.003mol); prepare according to the experimental procedure described in intermedium 10; recycle silicon glue carries out column chromatography, washs thus purification by hexane/ethyl acetate (from 100% to 50%), obtains the title compound (94%) of oily.
1H NMR(300MHz, )ppm 0.01(s,6H)0.85(br.s.,9H)1.31(br.s.,4H)1.43-1.59(m,4H)1.97(br.s.,2H)2.98(s,3H)3.38(br.s.,3H)3.48(br.s.,2H)3.57(br.s.,2H)4.31(br.s.,2H).
Intermedium 25
Trans-4-[3-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] propyl group } (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
By 3-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] propylmethanediyl sulfonate (intermedium 24; 0.74g, 0.001mol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.76g, 0.002mol) and triethylamine (0.6mL, 0.004mol) prepare according to the experimental procedure described in intermedium 6, recycle silicon glue carries out column chromatography, washs thus purification by chloroform/methanol 20/1, obtains the title compound (52%) of brown oil.
LRMS(m/z):624(M+1) +.
Intermedium 26
Trans-4-[{ 3-[(6-hydroxyl hexyl) oxygen base] propyl group } methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[(6-{ [tert-butyl (dimethyl) silicyl] oxygen base } hexyl) oxygen base] propyl group } (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 25; 0.7g, 0.001mol) and hydrochloric acid (1M, 4.3mL), prepare the title compound (98%) of brown solid according to the experimental procedure described in intermedium 19, gained coarse fodder does not need to be further purified, and for lower step.
LRMS(m/z):510(M+1) +
Intermedium 27
Trans-4-{ methyl [3-({ 6-[(methyl sulphonyl) oxygen base] hexyl } oxygen base) propyl group] is amino } cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[(6-hydroxyl hexyl) oxygen base] propyl group } methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 26; 0.57g; 0.001mol), triethylamine (0.22mL; 0.0012mmol) and methane sulfonyl chloride (0.1mL; 0.001mol); prepare according to the experimental procedure described in intermedium 10; recycle silicon glue carries out column chromatography, washs thus purification by chloroform/methanol 20/1, and obtains title compound as oil (78%).
LRMS(m/z):588(M+1) +
Intermedium 28
Trans-4-[[(13R)-13-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base)-15,15,16,16-tetramethyl-4,14-dioxa-11-azepine-15-silicon 16 alkyl-1-base] (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
Amino by trans-4-{ methyl [3-({ 6-[(methyl sulphonyl) oxygen base] hexyl } oxygen base) propyl group] } cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 27; 0.5g, 0.83mmol), 5-((1R)-2-amino-1-{ [tert-butyl (dimethyl) silicyl] oxygen base } ethyl)-8-oxyquinoline-2 (1H)-one (prepared by the preparation 8 according to US20060035931) (0.27g, 0.83mmol) and sodium bicarbonate (0.09g, 1.15mmol) prepare the title compound (10%) of brown oil according to the experimental procedure described in intermedium 7, gained coarse fodder does not need further process and for lower step.
LRMS(m/z):827(M+1) +
Example 5
Trans-4-[3-[(6-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base)-ethyl] is amino } hexyl) oxygen base] propyl group } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)-acetate hydrofluoride
By trans-4-[[(13R)-13-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base)-15,15,16,16-tetramethyl-4,14-dioxa-11-azepine-15-silicon 16 alkyl-1-base] (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 28; 0.35g, 0.09mmol) and triethylamine three hydrofluoride (0.46mL, 2.82mmol), prepare according to the experimental procedure described in example 1, carry out purification with preparing reversed-phase HPLC (system 2) again, and obtain the title compound (16%) of solid, shaped.
LRMS(m/z):712(M+1) +.
1H NMR(300MHz,DMSO-d 6).ppm 1.27(br.s.,4H)1.36(br.s.,2H)1.41-1.61(m,4H)1.69(br.s.,4H)1.91(br.s.,4H)2.12(s,3H)2.38(br.s.,2H)2.64(br.s.,3H)2.78(br.s.,2H)3.21-3.30(m,4H)4.69(br.s.,1H)5.10(br.s.,1H)6.52(d,J＝9.89Hz,1H)6.92(d,J＝8.24Hz,1H)6.97(dd,J＝5.08,3.71Hz,2H)7.07(dd,J＝3.57,1.37Hz,2H)7.07-7.10(m,1H)7.46(dd,J＝5.08,1.24Hz,2H)8.17(d,J＝10.16Hz,1H)
Intermedium 29
Trans-4-[[3-(4-formyl phenoxy group) propyl group] (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By 4-(3-bromine propoxyl group) benzaldehyde (prepared by the example 53 according to WO2008096127) (0.25g, 0.001mol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.25g, 0.0007mol) and triethylamine (0.19mL, 0.001mol), prepare according to the experimental procedure described in intermedium 6, recycle silicon glue carries out column chromatography, washs thus purification by chloroform/methanol 50/1, and obtains the title compound (66%) of yellow oily.
LRMS(m/z):514(M+1) +
Intermedium 30
Trans-4-[3-[4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl) phenoxy group] propyl group (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
By (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (24mg, 0.06mmol) joins trans-4-[[3-(4-formyl phenoxy group) propyl group] (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 29; 25mg, 0.05mmol) in the solution of oxolane (0.7mL), this mixture stirs 6 hours in 60 DEG C under nitrogen atmosphere.Be cooled to 0 DEG C, and add triacetyl oxygen sodium borohydride (32mg, 0.15mmol).Sodium bicarbonate solution 4% (2mL) stirred at ambient temperature whole evening, then adds in reaction vessel (pH=8) by mixture, and quenches by ethyl acetate and get coarse fodder.Organic layers with water and normal saline washing, in addition dry, filter, and solvent under reduced pressure removes, then obtain the title compound (99%) of oily, and it does not need to be further purified and for lower step.
LRMS(m/z):833(M+1) +
Example 6
Trans-4-[{ 3-[4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base)-ethyl] is amino } methyl) phenoxy group] propyl group } (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate formates (1:1)
By trans-4-[{ 3-[4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenoxy group] propyl group } (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 30; 0.21g, 0.21mmol) and triethylamine three hydrofluoride (0.12mL, 0.77mmol) prepare according to the experimental procedure described in example 1, then carry out purification with preparing reversed-phase HPLC (system 1), and obtain the title compound (54%) of faint yellow solid shape.
LRMS(m/z):718(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.37(br.s.,4H)1.61-2.01(m,6H)2.17(s,3H)2.35-2.45(m,2H)2.54(br.s.,1H)2.72(br.s.,2H)3.77(br.s.,2H)3.96(br.s.,2H)4.69(br.s.,1H)5.11(br.s.,1H)6.48(d,J＝9.89Hz,1H)6.83-6.89(m,2H)6.92(d,J＝7.97Hz,2H)6.98(br.s.,2H)7.03-7.12(m,3H)7.25(d,J＝8.51Hz,2H)7.46(d,J＝6.32Hz,1H)8.09(d,J＝9.89Hz,1H)8.27(s,1H,HCOOH)
Intermedium 31
4-(2-bromine oxethyl) benzaldehyde
Potassium carbonate (6.6g, 0.047mol) and glycol dibromide (21mL, 0.24mol) are added 4-oxybenzene formaldehyde (3g, 0.024mol) in the solution of ethanol (30mL).Stir 20 hours at 70 DEG C.Salt is filtered and its filtrate is concentrated, use acetic acid ethyl dissolution coarse fodder, and organic layers with water, sodium hydroxide 2N and saline are rinsed, dry, and filter.Under reduced pressure removed by organic solvent, to obtain the title compound (88%) of crocus solid, it does not need to be further purified and for lower step.
LRMS(m/z):230(M+1) +
Intermedium 32
Trans-4-[[2-(4-formyl phenoxy group) ethyl] (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By 4-(2-bromine oxethyl) benzaldehyde (intermedium 31; 0.5g, 0.002mol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.5g, 0.001mol) and triethylamine (0.39mL, 0.002mol), prepare according to the experimental procedure described in intermedium 6, recycle silicon glue carries out column chromatography, washs thus purification by chloroform/methanol (from 50:1 to 25:1), obtains the title compound (60%) of solid, shaped.
LRMS(m/z):500(M+1) +
Intermedium 33
Trans-4-[2-[4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl) phenoxy group] ethyl (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[[2-(4-formyl phenoxy group) ethyl] (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 32; 0.39g, 0.79mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2--dihydroquinoline-5-base)-second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (0.37g, 0.96mmol) and triacetyl oxygen sodium borohydride (0.5g, 2.38mmol), prepare the title compound (89%) of yellow solid according to the experimental procedure described in intermedium 30, gained coarse fodder does not need to be further purified and for lower step.
LRMS(m/z):819(M+1) +
Example 7
Trans-4-[{ 2-[4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenoxy group] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride
By trans-4-[{ 2-[4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenoxy group] ethyl } (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 33; 0.6g, 0.71mmol) and triethylamine three hydrofluoride (0.36mL, 2.22mmol) prepare according to the experimental procedure described in example 1, then with preparing reversed-phase HPLC (system 2) purification and obtain the title compound (44%) of faint yellow solid in addition.
LRMS(m/z):705(M+1) +.
1H NMR(300MHz,DMSO-d 6)δppm 1.30-1.47(m,4H)1.74(br.s.,2H)1.93(br.s.,2H)2.25(s,3H)2.42-2.48(m,4H)2.76(br.s.,4H)3.84(s,1H)3.98(t,J＝5.91Hz,2H)4.71(br.s.,1H)5.17(br.s.,1H)6.49(d,J＝9.89Hz,1H)6.84-6.94(m,3H)6.98(dd,J＝5.36,3.98Hz,2H)7.07(br.s.,4H)7.30(d,J＝8.24Hz,2H)7.47(d,J＝4.94Hz,1H)8.12(d,J＝9.89Hz,1H)
Intermedium 34
1-[4-(3-bromine propoxyl group) phenyl] acetone
By 1,3-dibromopropane (7.6mL, 0.07mol), potassium carbonate (2.3g, 0.01mol) and potassium iodide (0.7g, 0.004mol) join 1-(4-hydroxyphenyl) propane-2-ketone (2.2g, in solution 0.01mol) in dimethyl acyl ammonium (10mL), in stirred at ambient temperature 72 hours.Again water is added in reaction vessel, and quench by ethyl acetate and get coarse fodder.After organic layers with water and normal saline washing, dry, filter and be evaporated to dry.Gained coarse fodder silica gel carries out column chromatography, washs thus purification by hexane/ethyl acetate (by 100% to 10%), and obtains title compound (54%).
LRMS(m/z):272(M+1) +
Intermedium 35
Trans-4-(methyl { 3-[4-(2-oxygen propyl group) phenoxy group] propyl group } is amino) cyclohexyl hydroxyl (two-2-thienyls) acetate
By 1-[4-(3-bromine propoxyl group) phenyl] acetone (intermedium 34; 1g, 0.003mol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.6g, 0.002mol) and triethylamine (0.5mL, 0.004mol) prepare according to the experimental procedure described in intermedium 6, recycle silicon glue carries out column chromatography, washs thus purification with chloroform/methanol 25:1, obtains the title compound (84%) of brown yellow oil.
LRMS(m/z):542(M+1) +
Intermedium 36
Trans-4-[3-[4-(2-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino propyl group) phenoxy group] propyl group (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-(methyl { 3-[4-(2-oxygen propyl group) phenoxy group] propyl group } is amino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 35; 0.4g, 0.72mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (0.34g, 0.87mmol) and triacetyl oxygen sodium borohydride (0.4g, 1.84mol), prepare according to the experimental procedure described in intermedium 30, and obtaining the title compound (57%) of yellow foam, gained coarse fodder does not need to be further purified and for lower step.
LRMS(m/z):861(M+1) +
Example 8
Trans-4-[3-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base)-ethyl] is amino } propyl group) phenoxy group] propyl group } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride
By trans-4-[{ 3-[4-(2-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } propyl group) phenoxy group] propyl group } (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 36; 0.37g, 0.0002mol) and triethylamine three hydrofluoride (1mL, 0.01mol), prepare according to the experimental procedure described in example 1, again with preparing reversed-phase HPLC (system 2) and lyophilisation thus purification in addition, and obtain the title compound (50%) of yellow foam.
LRMS(m/z):746(M+1) +.
1H NMR(300MHz,DMSO-d 6).ppm 0.96(br.s.,4H)1.36(br.s.,3H)1.61-1.97(m,5H)2.18(br.s.,5H)2.43(br.s.,4H)2.86(br.s.,2H)3.03(br.s.,1H)3.93(br.s.,2H)4.68(br.s.,1H)5.15(br.s.,1H)6.53(d,J＝9.89Hz,1H)6.81(br.s.,2H)6.86-7.00(m,3H)7.06(br.s.,4H)7.25(br.s.,1H)7.46(br.s.,2H)8.20(br.s.,1H)
Intermedium 37
Ethyl 4-amino-5-chloro-2-methoxy benzoic acid salt
By the 4-amino-5-chloro-2-methoxy benzoic acid (6.6g in hydrogen chloride 1.25M, 0.031mol) at ethanol (250mL, stir 6 hours in pressure vessel at 65 DEG C in solution 0.31mol), then alkalize with 2N sodium hydroxide, and quench with methene chloride and get.Organic layers with water carries out drying after rinsing and filters.Solvent under reduced pressure removes, and obtains the title compound (78%) of white solid, and it does not need to be further purified and for lower step.
LRMS(m/z):230(M+1) +
Intermedium 38
(4-amino-5-chloro-2-anisyl) methanol
By the ethyl 4-amino-5-chloro-2-methoxy benzoic acid salt (intermedium 37 in oxolane (25mL); 4.4g, 0.019mol) instill under room temperature to the solution of Li-Al hydrogen compound (0.96g, 0.025mol) in oxolane (100mL).Then reflux 2 hours, the water of the water of unnecessary hydride 1ml, the 4N NaOH solution of 1ml and 2ml successively adds and removes, then filters with celite and use ethyl acetate rinse.Gained title compound is faint yellow solid (80%), and it does not need to be further purified and for lower step.
LRMS(m/z):188(M+1) +
Intermedium 39
4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-aminoanisole
Imidazoles (1.7g, 0.02mol) is added to (4-amino-5-chloro-2-anisyl) methanol (intermedium 38; 1.5g, 0.008mol) solution in dimethyl formamide (35mL).Mixture is cooled to 0 DEG C, then instills chloro (isopropyl) dimethylsilane (2.5g, 0.01mol).And stirred at ambient temperature whole evening.Remove solvent, coarse fodder is separated between water and hexane.Organic layers with water, 4% sodium bicarbonate and normal saline washing after, in addition dry, filter and be evaporated to dry, gained coarse fodder silica gel carries out column chromatography, washs thus purification by hexane/ethyl acetate (from 8/1 to 4/1), obtains the title compound (58%) of yellow solid.
LRMS(m/z):302(M+1) +
Intermedium 40
N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-acrylamide
The solution of acryloyl chloride compound (0.07mL, 0.91mmol) in methene chloride (1mL) is added dropwise to 4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-aminoanisole (intermedium 39; 0.2g, 0.68mmol) solution in methene chloride (2mL) and diethyl isopropyl amine (0.17mL, 1.02mmol).In stirred at ambient temperature 2 hours, then with methene chloride dilution, and with 4% sodium bicarbonate and water rinse, under reduced pressure remove desolventizing, the title compound (94%) of gained solid, shaped does not need to be further purified, and for lower step.
LRMS(m/z):356(M+1) +
Intermedium 41
Trans-4-((3-(4-((tert-butyl (dimethyl) siloxy) methyl)-2-chloro-5-methoxv-phenvlamino)-3-oxygen propyl group) (methyl) is amino) cyclohexyl hydroxyl (two-2-thienyls) acetate
By N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-acrylamide (intermedium 40; 0.9g, 0.002mol) and trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.7g, 0.002mol) mixture in methene chloride (20mL) stirs 64 hours in 75 DEG C in hermetic container.Evaporated by solvent, gained coarse fodder recycle silicon glue carries out column chromatography, washs by chloroform/methanol (by 50/1 to 25/1), thus purification, obtain the title compound (49%) of white-yellow solid.
LRMS(m/z):707(M+1) +
Intermedium 42
Trans-4-((3-(2-chloro-4-(methylol)-5-anisidino-)-3-oxygen propyl group)-(methyl) is amino) cyclohexyl hydroxyl (two-2-thienyls) acetate
Hydrochloric acid 1M (3.25mL, 3.25mmol) is joined trans-4-((3-(4-((tert-butyl (dimethyl) siloxy) methyl)-2-chloro-5-methoxv-phenvlamino)-3-oxygen propyl group) (methyl) is amino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 41; 0.76mg, 1.08mmol) solution in oxolane (19mL).Mixture, in stirred at ambient temperature 3 hours, then with saturated solution of sodium bicarbonate neutralization, and is quenched by ethyl acetate and is got.Gained coarse fodder silica gel carries out column chromatography, washs by chloroform/methanol 50/1, thus purification is to obtain the title compound (84%) of oily.
LRMS(m/z):593(M+1) +
Intermedium 43
Trans-4-((3-(2-chloro-4-formoxyl-5-anisidino-)-3-oxygen propyl group) (methyl)-amino) cyclohexyl hydroxyl (two-2-thienyls) acetate
Manganese oxide (IV) (0.62mg, 7.2mmol) is joined trans-4-((3-(2-chloro-4-(methylol)-5-anisidino-)-3-oxygen propyl group)-(methyl) is amino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 42; 0.4g, 0.68mmol) solution in chloroform (8.1mL), uneven mixture stirs 3 hours in 45 DEG C, then filter, under reduced pressure except desolventizing, obtain the title compound (88%) of yellow solid, it does not need to be further purified and for lower step.
LRMS(m/z):592(M+1) +
Intermedium 44
Trans-4-((3-(4-(((R)-2-(tert-butyl methyl silicane oxygen base)-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl)-2-chloro-5-anisidino-)-3-oxygen propyl group) (methyl) is amino) cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-((3-(2-chloro-4-formoxyl-5-anisidino-)-3-oxygen propyl group) (methyl)-amino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 43; 0.5g, 0.87mmol), (2R)-2-{ [tert-butyl (dimethyl)-silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (0.5g, 1.3mmol) and triacetyl oxygen sodium borohydride (0.66g, 3.15mmol), prepare according to the experimental procedure described in intermedium 30, and obtaining the title compound (84%) of faint yellow solid shape, it does not need to be further purified and for lower step.
LRMS(m/z):910(M+1) +
Example 9
Trans-4-((3-(2-chloro-4-(((2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl)-5-anisidino-)-3-oxygen propyl group) (methyl) is amino)-cyclohexyl hydroxyl (two-2-thienyls) acetate
Hydrofluoride
By trans-4-((3-(4-(((R)-2-(tert-butyl methyl silicane oxygen base)-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl)-2-chloro-5-anisidino-)-3-oxygen propyl group) (methyl) is amino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 44; 0.89g, 0.74mmol) and triethylamine three hydrofluoride (0.48mL, 2.98mmol), prepare according to the experimental procedure described in example 1, again with preparing reversed-phase HPLC (system 2) and lyophilisation purification in addition, obtain the title compound (19%) of white solid.
LRMS(m/z):796(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.42(br.s.,4H)1.76(br.s.,2H)1.94(br.s.,2H)2.27(s,3H)2.45-2.50(m,1H)2.59(br.s.,2H)2.72(br.s.,4H)3.64-3.76(m,5H)4.69(br.s.,1H)5.06(br.s.,1H)6.48(d,J＝9.89Hz,1H)6.87-6.94(m,2H)6.97(dd,J＝5.08,3.71Hz,2H)7.07(dd,J＝3.71,1.24Hz,2H)7.33(s,1H)7.47(dd,J＝5.08,1.24Hz,2H)7.79(s,1H)8.12(d,J＝9.89Hz,1H)10.67(s,1H)
Intermedium 45
(4-amino-3-chlorphenyl) methanol
By commercially available methyl 4-amino-3-chlorobenzene hydrochlorate (4g; 0.021mol) and Li-Al hydrogen compound (1.09g; 0.028mol) in the oxolane of 1.44ml, prepare according to the experimental procedure described in intermedium 38, and obtain light brown solid title compound (76%).
LRMS(m/z):158(M+1) +
Intermedium 46
4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloroaniline
By (4-amino-3-chlorphenyl) methanol (intermedium 45; 2.72g, 0.016mol), chloro (tert-butyl group)-dimethylsilane (4.94g, 0.033mmol) and imidazoles (3.35g, 0.049mol) in 68ml DMF, prepare according to the experimental procedure described in intermedium 39, and obtain the title compound (87%) of light orange oily.
LRMS(m/z):272(M+1) +
Intermedium 47
N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chlorphenyl] acrylamide
By 4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloroaniline (intermedium 46; 2g; 7.36mmol), acryloyl chloride compound (0.78ml; 9.56mmol) and diethylisopropylamide (1.92ml, 11.04mmol), prepare according to the experimental procedure described in intermedium 40, and obtain the title compound (77%) of white crystalline solid.
LRMS(m/z):326(M+1) +
Intermedium 48
Trans-4-((3-(4-((tert-butyl (dimethyl) siloxy) methyl)-2-chloroanilino)-3-oxygen propyl group) (methyl) is amino) cyclohexyl hydroxyl (two-2-thienyls) acetate
By N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chlorphenyl] acrylamide (intermedium 47; 0.56g, 1.73mmol) and trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.5g, 1.42mmol) in the dichloromethane of 14ml, prepare according to the experimental procedure described in intermedium 41, and obtain the title compound (45%) of beige solid shape.
LRMS(m/z):677(M+1) +
Intermedium 49
Trans-4-((3-(2-chloro-4-(methylol)-phenylamino)-3-oxygen propyl group) (methyl)-amino) cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-((3-(4-((tert-butyl (dimethyl) siloxy) methyl)-2-chloroanilino)-3-oxygen propyl group) (methyl) is amino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 48; 433mg, 0.64mmol) and 1M hydrochloric acid (1.9ml; 1.9mmol) in oxolane (12mL), prepare according to the experimental procedure described in intermedium 42, obtain the foamed title compound of taupe brown (91%).
LRMS(m/z):563(M+1) +
Intermedium 50
Trans-4-((3-(2-chloro-4-formoxyl-phenylamino)-3-oxygen propyl group) (methyl) is amino)-cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-((3-(2-chloro-4-(methylol)-phenylamino)-3-oxygen propyl group) (methyl)-amino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 49; 0.06g, 0.11mmol) and manganese oxide (IV) (0.098mg, 1.13mmol) in chloroform (1.4mL), prepare according to the experimental procedure described in intermedium 43, and obtain the title compound (94%) of pale brown oil.
LRMS(m/z):561(M+1) +
Intermedium 51
Trans-4-((3-(4-(((R)-2-(tert-butyl methyl silicane oxygen base)-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl)-2-chloroanilino)-3-oxygen propyl group) (methyl)-amino) cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-((3-(2-chloro-4-formoxyl-phenylamino)-3-oxygen propyl group) (methyl) is amino)-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 50; 54mg, 0.10mmol), (2R)-2-{ [tert-butyl (dimethyl)-silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (57mg, 0.14mmol) and triacetyl oxygen sodium borohydride (77mg, 0.35mmol), prepare according to the experimental procedure described in intermedium 30, again with preparing reversed-phase HPLC (CHCl3 to CHCl3/MeOH95:5) purification, obtain the title compound (65%) of white solid.
LRMS(m/z):879(M+1) +
Example 10
Trans-4-((3-(2-chloro-4-(((2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl) phenylamino)-3-oxygen propyl group) (methyl) is amino)-cyclohexyl-hydroxy (two-2-thienyls) acetate hydrofluoride
By trans-4-((3-(4-(((R)-2-(tert-butyl methyl silicane oxygen base)-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl)-2-chloroanilino)-3-oxygen propyl group) (methyl)-amino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 51; 55mg, 0.06mmol) and triethylamine three hydrofluoride (0.04mL, 0.25mmol) in the THF of 3ml, prepare according to starving experimental procedure described in example 1, again with preparing reversed-phase HPLC (system 2) and lyophilisation carrys out purification, and obtain the title compound (20%) of beige solid.
LRMS(m/z):765(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.42(br.s.,4H)1.80(br.s.,2H)1.94(br.s.,2H)2.27(s,3H)2.45-2.50(m,1H)2.59(br.s.,2H)2.76(br.s.,4H)3.64-3.76(m,2H)4.69(br.s.,1H)5.31(br.s.,1H)6.54(d,J＝9.89Hz,1H)6.92-6.97(m,2H)6.98-7.12(m,5H)7.25(s,1H)7.44(dd,J＝5.08,1.24Hz,2H)7.65(s,1H)9.08(br.s.,1H)10.47(s,1H)
Intermedium 52
5-chloro-4-hydroxyl-2-methoxy benzoic acid
Tetrahydrochysene boric acid (48% aqueous solution of 40.5ml) is added to 4-amino-5-chloro-2-methoxy benzoic acid (25g; Suspension 0.12mol) in the water of 125ml.Then, white cake block is cooled to 0 DEG C, and instillation NaNO2 (9.41g is in the water of 75mL), and stir 30 minutes.Again by collecting by filtration white depositions, diazol is then suspended in ice AcOH (1250mL), and suspension is stirred 1 hour (it becomes brown solution) in 100 DEG C.It can at room temperature maintain more than 2 hours.Under reduced pressure except desolventizing, brown oil residue is then suspended in saline (1250ml), quenches get with EtOAC (3x400ml).In conjunction with organic layer over magnesium sulfate dry, filter and vapourisation under reduced pressure, and obtain brown oil, again with preparing reversed-phase HPLC (Et2O/EtOH 0/100 to 40/60) purification in addition, and obtain the red solid (13%) of 3.0g.
LRMS(m/z):203(M+1) +
Intermedium 53
Methyl 5-chloro-4-hydroxyl-2-methoxy benzoic acid salt
The acetyl group chloride of 2.2ml is joined 5-chloro-4-hydroxyl-2-methoxy benzoic acid (intermedium 52; 4.17g; Solution 13.69mmol) in 123ml absolute methanol.Solution stirs 18 hours in 60 DEG C under nitrogen atmosphere, then, under reduced pressure by solution evaporation, residue is then with preparing reversed-phase HPLC (Cl2CH2/EtOAc is from 100/0 to 80/20) purification in addition, and obtain the title compound (2.2g, 75%) of red solid.
LRMS(m/z):217(M+1) +
Intermedium 54
2-chloro-4-(methylol)-5-methoxy phenol
By methyl 5-chloro-4-hydroxyl-2-methoxy benzoic acid salt (intermedium 53; 204mg; The outside ice/water bath cooling of solution 0.94mmol) in the anhydrous THF of 4.6ml is also stirred.Solution (the 1.9ml of instillation 1M LiAlH4 in THF; 1,9mmol).After 5 minutes, remove outer bath, then stir 3 hours.Along with external refrigeration, add the water of 0.072ml, then add the 4N NaOH solution of 0.072ml, add again the water of 0.144ml.After filtration, with THF cleaning down filter cake, filtrate is concentrated, then obtain title compound (34% productive rate).
LRMS(m/z):189(M+1) +
Intermedium 55
[4-(3-bromine propoxyl group)-5-chloro-2-anisyl] methanol
By 2-chloro-4-(methylol)-5-methoxy phenol (intermedium 54; 0.5g, 2.61mmol), 1,3-dibromopropane (1.61ml; 15.71mmol) and potassium carbonate (737mg; Mixture 5.23mmol) in the acetone of 12ml is heated to 75 DEG C and stirs 16 hours in hermetic container.Leaching solid with acetone rinsing, in conjunction with filtrate be then concentrated to dry, then with preparing reversed-phase HPLC (hexane/EtOAc is by 0 to 40%) in addition purification, and obtain the title compound (80%) of faint yellow oily.
LRMS(m/z):309(M+1) +
Intermedium 56
Trans-4-[{ 3-[2-chloro-4-(methylol)-5-methoxy phenoxy] propyl group } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By [4-(3-bromine propoxyl group)-5-chloro-2-anisyl] methanol (intermedium 55; 386mg; 1.25mmol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 438mg, 1.25mmol) and triethylamine (0.345ml; Mixture 2.49mmol) in the acetonitrile of 12ml and the THF of 8.7ml stirs 16 hours in 70 DEG C, then adds extra intermedium 5 (219mg; 0.62%mmol), and heat 24 hours.Solvent evaporates under vacuum, and residue then with preparing reversed-phase HPLC (hexane/EtOAc is from 0 to 40%) purification in addition, obtains the title compound (80%) of faint yellow oily.
LRMS(m/z):309(M+1) +
Intermedium 57
Trans-4-[[3-(2-chloro-4-formoxyl-5-methoxy phenoxy) propyl group] (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[2-chloro-4-(methylol)-5-methoxy phenoxy] propyl group } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 56; 418mg, 0.70mmol) and manganese oxide (IV) (755mg; Mixture 7.38mmol) in the chloroform of 9ml stirs 3 hours in 45 DEG C.By solid leaching and with chloroform rinse, filtrate is then concentrated to dry, and obtains the title compound (97%) of colorless oil.
LRMS(m/z):307(M+1) +
Intermedium 58
Trans-4-[3-[4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2-chloro-5-methoxy phenoxy] propyl group-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[[3-(2-chloro-4-formoxyl-5-methoxy phenoxy) propyl group] (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 57; 401mg; 0.69mmol), (2R)-2-{ [tert-butyl (dimethyl)-silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline 5-yl) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (346mg, 0.88mmol) and triacetyl oxygen sodium borohydride (557mg, 2.50mmol), prepare according to the experimental procedure described in intermedium 30, then with preparing reversed-phase HPLC (CHCl3 to CHCl3/MeOH 95:5) purification and obtain the title compound (73%) of colorless oil in addition.
LRMS(m/z):896(M+1) +
Example 11
Trans-4-[{ 3-[2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxy phenoxy] propyl group } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride
By trans-4-[{ 3-[4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-2-chloro-5-methoxy phenoxy] propyl group }-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 58; 59mg, 0.06mmol) and triethylamine three hydrofluoride (0.04mL, 0.28mmol) in the THF of 3ml, prepare according to the experimental procedure described in example 1, again with preparing reversed-phase HPLC (system 2) and lyophilisation purification in addition, and obtain the title compound (72%) of beige solid.
LRMS(m/z):782(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.36(m.,4H)；1.70(b.s.,2H)；1.82(m.,2H)；1.89(b.s.；2H)；2.17(s.,3H)；2.37(b.s.,1H)；2.54(m.,2H)；2.63(m.,2H)；3.17(b.s.,1H)；3.52(m.,2H)；3.76(s.,3H)；4.09(t.,2H)；4.68(b.s.,1H)；5.01(m.,1H)；6.47(d.,1H)；6.7(s.,1H)；6.90(d.,1H)；6.93-7.09(c.s.,5H)；7.24(s.,1H)；7.46(d.,1H)；8.11(d.,1H).
Intermedium 59
Tert-butyl [(5-chloro-4-isocyanate group-2-anisyl) oxygen base] dimethylsilane
4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-aminoanisole (intermedium 39; 300mg, 1mmol) solution in the dichloromethane of 4ml with the capable external refrigeration of ice bath, instill triphosgene (108mg simultaneously; Solution 0.36mmol) in the dichloromethane of 5ml, more slowly add triethylamine (0.28ml; 2.01mmol), and in stirred at ambient temperature 3 hours.Vaporising under vacuum falls the solvent of half, and adds the pentane of 25ml.The white precipitate of leaching carbamide, evaporation of filtrate to dry, and obtains the title compound of 311mg, and it does not need to be further purified and for lower step.
Intermedium 60
Trans-4-[(2-ethoxy) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
Trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 300mg; 0.85mmol), ethylene bromohyrin (0.145ml; 2.05mmol) and triethylamine (0.36ml; Mixture 2.58mmol) in the acetonitrile of 4.5ml and the THF of 3.5ml stirs 16 hours in 80 DEG C in hermetic container, then adds extra bromoethanol (0.145ml; 2.05mmol), triethylamine (0.36ml; 2.58mmol), acetonitrile (3.5ml) and THF (3.5ml), and stir, heat 24 hours.Again with preparing reversed-phase HPLC (Cl3CH/MeOH is from 1:0 to 9:1) purification, and obtain the title compound (76%) of colorless oil.
LRMS(m/z):396(M+1) +
Intermedium 61
Trans-4-[{ 2-[({ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-methoxy-phenyl] is amino } hydroxyl) oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(2-ethoxy) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 60; 290.6mg; Solution 0.73mmol) in the THF of 5ml is in stirred at ambient temperature and instill tert-butyl [(5-chloro-4-isocyanate group-2-anisyl) oxygen base] dimethylsilane (intermedium 59; 311mg; Solution 0.87mmol) in the THF of 5ml, then add triethylamine (0.228ml; 1.31mmol), and stir 16 hours in 60 DEG C, then stir 4 hours in 80 DEG C.Solution is concentrated, and with preparing reversed-phase HPLC (CH 2cl 2/ isopropyl alcohol 10:0 to 9:1) purification in addition, obtain the title compound of 66%.
LRMS(m/z):723(M+1) +
Intermedium 62
Trans-4-[{ 2-[({ [2-chloro-4-(methylol)-5-anisyl] is amino } carbonyl)-oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
The moisture 1M HCl (1.31mmol) of 1.31ml is joined trans-4-[{ 2-[({ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-methoxy-phenyl] is amino } hydroxyl) oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 61; 315mg; Solution 0.44mmol) in the THF of 6ml, and in stirred at ambient temperature 2.5 hours, then alkalized with the sodium bicarbonate aqueous solution of 4%, and quench by ethyl acetate and get three times.Organic quenching gets thing normal saline washing, drier and concentrated, with preparing reversed-phase HPLC (CH2Cl2 isopropyl alcohol 10:0 to 9:1) in addition purification, and obtains the title compound of 78%.
LRMS(m/z):609(M+1) +
Intermedium 63
Trans-4-[[2-({ [(2-chloro-4-formoxyl-5-anisyl) is amino] carbonyl } oxygen base) ethyl]-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 2-[({ [2-chloro-4-(methylol)-5-anisyl] is amino } carbonyl)-oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 62; 200mg; 0.33mmol) be dissolved in the difluoromethane of 8ml, and in stirring at room temperature under noble gas atmosphere.By Dess-Martin reagent (170mg; 0.40mmol) add, and stir 30 minutes, then add dichloromethane (15ml), then with 4% sodium bicarbonate aqueous solution flushing, and vigorous stirring 1 hour.Leaching solid, the filtrate of organic facies then uses normal saline washing, drier, and concentrated and obtain the title compound of 197mg.Its purity is enough for lower step.
LRMS(m/z)：607(M+1) +
Intermedium 64
Trans-4-[2-[([4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base } 2-2 (8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2-chloro-5-anisyl] amino-carbonyl) oxygen base] ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[[2-({ [(2-chloro-4-formoxyl-5-anisyl) is amino] carbonyl } oxygen base) ethyl]-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 63; 195mg; 0.28mmol) and (2R)-2-{ [tert-butyl (dimethyl)-silicyl] oxygen base-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (119mg, 0.36mmol) solution in the THF of 5ml in 65 DEG C stir 20 hours.After being cooled with an ice bath, by triacetyl oxygen sodium borohydride (195mg; 0.92mol) piecemeal adds, then stirs 15 minutes in 5 DEG C, and again in stirred at ambient temperature 45 minutes.Solution is condensed into half volume, and add the sodium bicarbonate aqueous solution of the water of 15ml and 4% of 15ml, quench by ethyl acetate again and get mixture three times, and with normal saline washing, dry again and concentrated, residue with preparing reversed-phase HPLC (CHCl3/ isopropyl alcohol 10:0 to 9:1) purification, and obtains the title compound of 47%.
LRMS(m/z):925(M+1) +
Example 12
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl) oxygen base] ethyl }-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride
By triethylamine three hydrofluoride (0.04mL, 0.28mmol) join trans-4-[{ 2-[({ [4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base } 2-2 (8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-2-chloro-5-anisyl] is amino }-carbonyl) oxygen base] ethyl } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 64; 125mg; Solution 0.14mmol) in 5ml THF, stirred after 20 hours, removed by liquid level, and residue stirred 1 hour with 5ml THF again, then removed liquid level.Afterwards, add acetonitrile (15ml), and stir 1 hour.Leaching solid, and rinse with acetonitrile and diisopropyl ether, and obtain pure title compound (67%).
LRMS(m/z):811(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.06(d.,J＝6Hz,2H)；1.39(m.,3H)；1.75(m.,2H)；1.93(m.,2H)；2,24(s.,3H)；2.44(b.s.,1H)；2.67(m.,2H)；2.76(m.,2H)；3.78(m.,5H)；4.13(m.,2H)；4.72(b.s.,1H)；5.14(t.,1H)；6.52(d.,J＝12Hz,1H)；6.90-7.03(m.,3H)；7.09(m.,3H)；7.23(s.,1H)；7.28(b.s.,1H)；7.40(s.,1H)；7.49(d.,J＝6Hz；1H)；8.15(d.,J＝12Hz,1H)；9.01(s.,1H)；10.39(b.s.,1H).
Intermedium 65
N, N-diphenyl-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl-8-amine diphenyl (Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl-8-base) amine
By diphenylamines (32.3mL, 0.16mol) be added to 1 in a hydrogen atmosphere, 4-dioxo spiro [4.5] decyl-8-ketone (25g, 0.16mol) 1, solution in 2-dichloroethanes (396mL), and in stirred at ambient temperature 2 hours, then by triacetyl oxygen sodium borohydride (55.4g, 0.25mol) a part ofly to add, and stirred at ambient temperature whole evening, add the mixture of two carbonate and dichloromethane (1:1) again, and stir 1 and a half hours, afterwards, quench and get organic facies, and with two carbonate and normal saline washing, dry, filter, vapourisation under reduced pressure organic solvent.Use the grease of hexane precipitating gained again, obtain the title compound (80%) of white solid, it does not need to be further purified, and for lower step.
LRMS(m/z):338(M+1) +
Intermedium 66
4-(diphenylamino) Ketohexamethylene
By N, N-diphenyl-Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl-8-amine diphenyl (Isosorbide-5-Nitrae-dioxo spiro [4.5] decyl-8-base) amine (intermedium 65; 43.6g, 0.13mol) be suspended in hydrochloric acid (35%, 49.4mL, 0.59mol), mixture stirs 8 hours in 100 DEG C.Afterwards, cool with frozen water, and with potassium carbonate alkalization until pH ~ 8, quench with chloroform again and get, organic facies is evaporated to dry, and the grease silica gel of gained carries out column chromatography, washs by hexane/ethyl acetate (from 98/2 to 90/10), thus purification, obtain the title compound (72%) of yellow solid.
LRMS(m/z):294(M+1) +
Intermedium 67
Trans-4-(diphenylamino)-1 methyl cyclohexanol
Lithium methide 1.6M in diethyl ether (30mL, 48mmol) is slowly added to 4-(diphenylamino) Ketohexamethylene (intermedium 66 under an argon atmosphere in-78 DEG C; 10g, 32mmol) solution in anhydrous oxolane, and stir 4 hours in-78 DEG C.Then, add the saturated solution of ammonium chloride, then stirred at ambient temperature whole evening.By organic solvent evaporation, gained coarse fodder water and chloroform are processed.Then, organic layers with sodium sulfate is dry, filter and evaporate, to obtain grease, recycle silicon glue carries out column chromatography, with hexane/ethyl acetate (by the ethyl acetate of 0% hexane to 31%) washing, thus purification, obtain two kinds of different products, the first corresponds to cis-product, and the second is the trans product of white solid and is title compound (55%).
LRMS(m/z):310(M+1) +
Intermedium 68
Trans-4-amino-1 methyl cyclohexanol
Palladium dydroxide (1.7g, 2.44mmol) is added in a nitrogen atmosphere trans-4-(diphenylamino)-1 methyl cyclohexanol (intermedium 67; 5.7g, 17.68mmol) in anhydrous ethanol (125mL), starve solution.Afterwards, in a hydrogen atmosphere room temperature vigorous stirring whole evening.Mixture is filtered by celite, and with alcohol flushing, vapourisation under reduced pressure solvent, and obtains the title compound (98%) of white solid, and it does not need to be further purified and for lower step.
LRMS(m/z):130(M+1) +
Intermedium 69
Tert-butyl (trans-4-hydroxy-4-methyl cyclohexyl) carbaminate
Two-tert-butyl two carbonate (4.3g, 20.11mmol) is added under an argon atmosphere trans-4-amino-1 methyl cyclohexanol (intermedium 68; 2.3g, 18.27mmol) in the suspension of acetonitrile (33mL).Mixture vigorous stirring under room temperature whole evening.Leaching precipitate also uses hexane: ethyl acetate (3:1) is rinsed.Gained solid recycle silicon glue carries out column chromatography, with hexane: ethyl acetate (ethyl acetate by 0% to 100%) is washed, thus purification, obtain the title compound (90%) of white solid.
1H NMR(300MHz,CHLOROFORM-d)
Intermedium 70
Trans-1-methyl-4-(methylamino) Hexalin
By tert-butyl (trans-4-hydroxy-4-methyl cyclohexyl) carbaminate (intermedium 69; 3.6g, 16.09mmol) add the suspension of Li-Al hydrogen compound (3.1g, 82.21mmol) in anhydrous oxolane of room temperature.Mixture refluxes whole evening, then cool to room temperature, eliminates unnecessary hydride and filters.Under reduced pressure except desolventizing, and the grease that must solidify.This solid is then title compound (98%).
1H NMR(300MHz,CHLOROFORM-d)
Intermedium 71
Tert-butyl (trans-4-hydroxy-4-methyl cyclohexyl) methyl carbamic acid salt
By trans-1-methyl-4-(methylamino) Hexalin (intermedium 70; 2.5g, 17.4mmol) and two-tert-butyl two carbonate (4.1g, 19.2mmol) prepare (response time: 2 hours) according to the experimental procedure described in intermedium 69, recycle silicon glue carries out column chromatography, wash by chloroform/methanol (1:1), thus purification, and obtain title compound.
1H NMR(300MHz,CHLOROFORM-d)
Intermedium 72
Trans-4-[(uncle-butoxy carbonyl) (methyl) is amino]-1-methylcyclohexyl oxygen base (2-thienyl)-acetate
By oxalyl chloride compound (1.78mL, 20.47mmol) solution in chloroform/amylene instills to 2-oxo-2-(thiophene-2-base) acetic acid (2.13g, 13.64mmol) in the chloroform stable with amylene (25mL) and the solution of the anhydrous dimethylformamide of two under low temperature.Mixture is in low temperature 15 minutes and in stirred at ambient temperature 2 hours.Afterwards, be evaporated to by mixture dry, gained coarse fodder anhydrous methene chloride (21mL) dissolves, and under low temperature, instill tert-butyl (trans-4-hydroxy-4-methyl cyclohexyl) methyl carbamic acid salt (intermedium 71; 2.77g, 11.3mmol) solution in anhydrous methene chloride (25mL) and triethylamine (3.9mL, 28.42mmol).Mixture is stirred at ambient temperature whole evening, and coarse fodder is separated between water and methene chloride.Rinse organic layer with 4% bicarbonate and water, filter, and be evaporated to dry, and obtaining brown oil, recycle silicon glue carries out column chromatography, with hexane: ethyl acetate (1:1) is washed, thus purification, and obtain the title compound (62%) of orange oily.
LRMS(m/z):382(M+1) +
Intermedium 73
Trans-4-[(uncle-butoxy carbonyl) (methyl) is amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls) acetate
First by the 2-bromothiophene (0.83mL of 20%, solution 8.57mmol) in anhydrous oxolane (9.8mL) instills magnesium (0.21g under an argon atmosphere, suspension 8.64mmol) in anhydrous oxolane (14.7mL), instills the solution of remaining 2-bromothiophene again after a few minutes.Mixture is stirred 1 hour in 75 DEG C, afterwards, cool to room temperature, and under low temperature, instill trans-4-[(uncle-butoxy carbonyl) (methyl) is amino]-1-methylcyclohexyl oxo (2-thienyl)-acetate (intermedium 72 again; 2.65g, 6.6mmol) solution in anhydrous oxolane (18.4mL).Afterwards, mixture immediately in stirred at ambient temperature 1 hour, and refluxes 1 hour.Afterwards, cooling coarse fodder reactant also adds the saturated solution of ammonium chloride, then quenches with ether and get coarse fodder, and use normal saline washing organic layer, and dry and filtration.Organic solvent is then under reduced pressure removed, the capable column chromatography of gained coarse fodder recycle silicon glue, with hexane: ethyl acetate (1:1) is washed, in addition purification, and obtains the title compound (92%) of orange oily.
LRMS(m/z):466(M+1) +
Intermedium 74
Trans-1-methyl-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(uncle-butoxy carbonyl) (methyl) is amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 73; 0.18g, 0.39mmol) and hydrogen chloride 4M at dioxanes (0.49mL, solution 1.96mmol), prepare according to the experimental procedure described in intermedium 5, gained coarse fodder recycle silicon glue carries out column chromatography, and with chloroform/methanol (1:1) washing, in addition purification, and obtain the title compound of solid.
LRMS(m/z):366(M+1) +
Intermedium 75
Trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-amino }-3-oxygen propyl group) (methyl) amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls)-acetate
By trans-1-methyl-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 74; 92mg, 0.24mmol) and N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-acrylamide (intermedium 40; 104mg, 0.29mmol), prepare according to the experimental procedure described in intermedium 41, the capable column chromatography of gained coarse fodder recycle silicon glue, and with chloroform/hexane (1:1) washing, in addition purification, and obtain the title compound (69%) of yellow oily.
LRMS(m/z):722(M+1) +
Intermedium 76
Trans-4-[(3-{ [2-chloro-4-(methylol)-5-anisyl] is amino }-3-oxygen propyl group)-(methyl) amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-amino }-3-oxygen propyl group) (methyl) is amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls)-acetate (intermedium 75; 119mg, 0.16mmol) and 1M hydrochloric acid (0.49mL, 0.5mmol), prepare according to the experimental procedure described in intermedium 42, the capable column chromatography of gained coarse fodder recycle silicon glue, again with chloroform/methanol (15:1) washing, in addition purification, and obtain the title compound (73%) of colorless oil.
LRMS(m/z):608(M+1) +
Intermedium 77
Trans-4-[{ 3-[(2-chloro-4-formoxyl-5-anisyl) is amino]-3-oxygen propyl group }-(methyl) is amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(3-{ [2-chloro-4-(methylol)-5-anisyl] amino }-3-oxygen propyl group)-(methyl) is amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 76; 432mg, 0.7mmol) and manganese oxide (IV) (754mg, 7.37mmol), prepare according to the experimental procedure described in intermedium 43, and obtaining the title compound (97%) of colorless oil, it does not need to be further purified and for lower step.
LRMS(m/z):606(M+1) +
Intermedium 78
Trans-4-[(3-{ [4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2-chloro-5-anisyl] amino-3-oxygen propyl group) (methyl) amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[(2-chloro-4-formoxyl-5-anisyl) is amino]-3-oxygen propyl group }-(methyl) is amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 77; 0.4g, 0.67mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (0.4g, 1.01mmol) and triacetyl oxygen sodium borohydride (0.54g, 2.41mmol) prepare according to the experimental procedure described in intermedium 30, the capable column chromatography of recycle silicon glue, wash with chloroform/methanol (10:1), purification in addition, and obtain the title compound (85%) of colorless oil.
LRMS(m/z):924(M+1) +
Example 13
Trans-4-[(3-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino }-3-oxygen propyl group) (methyl) amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls) acetate
Amino by trans-4-[(3-{ [4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-2-chloro-5-anisyl] }-3-oxygen propyl group) (methyl) amino]-1-methylcyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 78; 0.43g, 0.46mmol) and triethylamine three hydrofluoride (0.32mL, 1.98mmol), prepare according to the experimental procedure described in example 1, again with preparing reversed-phase HPLC (system 2) purification in addition, and obtain the title compound (62%) of colorless oil.
LRMS(m/z):809(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.45(br.s.,11H)1.70(t.,3H)1.96(br.s.,3H)2.24(s,3H)2.45-2.50(b.s.,3H)2.63-2.77(m.,5H)3.63-3.70(m,4H)4.11(m,1H)5.02(m,1H)5.34(br.s.,1H)6.47(d,J＝9.89Hz,1H)6.89(m,2H)6.97(dd,J＝5.08,3.71Hz,2H)7.07(dd,J＝3.71,1.24Hz,2H)7.30(s,1H)7.45(dd,J＝5Hz,2H)7.68(s,1H)8.12(d,J＝9Hz,1H)10.36(b.s,2H)
Intermedium 79
N-[4-(methylol) phenyl] acrylamide
By (4-aminophenyl) methanol (0.5g; 4.06mmol), acryloyl group chloride (0.3mL; 4.06mmol) and diethyl isopropyl amine (1.4mL; 8.1mmol); prepare the title compound (82%) of solid, shaped according to the experimental procedure described in intermedium 40, gained coarse fodder does not need to be further purified and for lower step.
LRMS(m/z):178(M+1) +
Intermedium 80
Trans-4-[(3-{ [4-(methylol) phenyl] is amino }-3-oxygen propyl group) (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.5g, 1.42mmol) join N-[4-(methylol) phenyl] acrylamide (intermedium 79; 0.3g, 1.7mmol) solution in oxolane (6mL), mixture is put into hermetic container and is stirred 4 days in 75 DEG C.Solvent is under reduced pressure removed, and gained coarse fodder with preparing reversed-phase HPLC (system 2) purification in addition, and obtains title compound (34%).
LRMS(m/z):529(M+1) +
Intermedium 81
Trans-4-[{ 3-[(4-formylphenyl) is amino]-3-oxygen propyl group } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(3-{ [4-(methylol) phenyl] amino }-3-oxygen propyl group) (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 80; 0.25g, 0.47mmol) and manganese oxide (IV) (0.4g, 4.7mmol) prepare according to the experimental procedure described in intermedium 43, and title compound as oil (96%), it does not need to be further purified and for lower step.
LRMS(m/z):527(M+1) +
Intermedium 82
Trans-4-[(3-{ [4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl) phenyl] amino-3-oxygen propyl group) (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[(4-formylphenyl) is amino]-3-oxygen propyl group } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 81; 0.24g, 0.46mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (0.2g, 0.68mmol) and triacetyl oxygen sodium borohydride (0.34g, 1.64mmol), prepare according to the experimental procedure described in intermedium 30, the capable column chromatography of gained coarse fodder recycle silicon glue, in addition purification and obtain foamed title compound (31%).
LRMS(m/z):846(M+1) +
Example 14
Trans-4-[(3-{ [4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base-) ethyl] is amino } methyl) phenyl] is amino }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2)
Amino by trans-4-[(3-{ [4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] }-3-oxygen propyl group) (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 82; 0.12g, 0.14mmol) and triethylamine three hydrofluoride (0.07mL, 0.43mmol), prepare according to the experimental procedure described in example 1, again to prepare reversed-phase HPLC (system 2) purification in addition, and obtain the title compound (82%) of colorless oil.
LRMS(m/z):731(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.34-1.46(br.s.,4H)1.76(m,1H)1.94(br.s.,2H)2.27(br.s.,3H)2.48-2.52(b.s.5H)2.72–2.92(m,2H)4.71(m.,1H)5.26(br.s.,1H)6.52(d,J＝9Hz,1H)6.91-7.00(m.,3H)7.05.-7.11(m.,3H)7.27(s.1H)7.36–7.42(m,2H)7.47(d,J＝6Hz,1H)7.57(d,J＝9Hz,1H)8.10(dd,J＝5.08,1.24Hz,1H)10.15(br.s.,1H)10.44(s,1H)
Intermedium 83
The bromo-N-of 4-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-butyramide
4-bromobutanol chloride (0.32mL, 2.76mmol) is added 4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-aminoanisole (intermedium 39 in 0 DEG C in a nitrogen atmosphere; 0.75g, 2.48mmol) in oxolane (20mL) and the solution of triethylamine (0.38mL, 2.73mmol).Then, stir 1 and a half hours, then add ethyl acetate, and dry with two carbonate and normal saline washing organic layer, and solvent is under reduced pressure removed, then obtain title compound (97%), it does not need to be further purified, and for lower step.
LRMS(m/z):451(M+1) +
Intermedium 84
Trans-4-[(4-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-amino }-4-butyl) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By the bromo-N-of 4-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-butyramide (intermedium 83; 2.2g, 4.4mmol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 1.03g, 2.84mmol) and triethylamine (1.2mL, 8.82mmol), prepare according to the experimental procedure described in intermedium 6, gained coarse fodder again with the anti-phase HPCL of preparation (system 2) in addition purification, and obtains the title compound (4%) of oily.
LRMS(m/z):722(M+1) +
Intermedium 85
Trans-4-[(4-{ [2-chloro-4-(hydroxymethyl)-5-anisyl] is amino }-4-oxygen-butyl)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(4-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-amino }-4-butyl) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 84; 90mg, 0.12mmol) solution in oxolane (3.5mL), mixture is stirred at ambient temperature whole evening.Solvent is under reduced pressure removed, and gained coarse fodder again to prepare reversed-phase HPLC (system 2) purification in addition, and obtains title compound (23%).
LRMS(m/z):608(M+1) +
Intermedium 86
Trans-4-[{ 4-[(2-chloro-4-formoxyl-5-anisyl) is amino]-4-oxygen-butyl } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(4-{ [2-chloro-4-(hydroxymethyl)-5-anisyl] amino }-4-oxygen-butyl)-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 85; 0.68g, 1.12mmol) and manganese oxide (IV) (1.95g, 22.39mmol), prepare (response time: 32 hours) according to the experimental procedure described in intermedium 43.Gained coarse fodder is the title compound (84%) of oily, and it does not need to be further purified and for lower step.
LRMS(m/z):606(M+1) +
Intermedium 87
Trans-4-[(4-{ [4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2--dihydroquinoline-5-base) ethyl] amino methyl)-2-chloro-5-anisyl] amino-4-oxygen-butyl) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 4-[(2-chloro-4-formoxyl-5-anisyl) is amino]-4-oxygen-butyl } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 86; 0.35g, 0.4mmol), 5-((1R)-2-amino-1-{ [tert-butyl (dimethyl)-silicyl] oxygen base } ethyl)-8-oxyquinoline-2 (1H)-one (prepared by the preparation 8 according to US20060035931) (0.2g, 0.51mmol) and triacetyl oxygen boron hydride (0.28g, 1.32mmol), prepare according to the experimental procedure described in intermedium 30, gained coarse fodder recycle silicon glue carries out column chromatography, wash with chloroform/methanol (95:5), purification in addition, and obtain the title compound (47%) of brown solid.
LRMS(m/z):924(M+1) +
Example 15
Trans-4-[(4-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino }-4-oxygen-butyl) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
Amino by trans-4-[(4-{ [4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2--dihydroquinoline-5-base) ethyl] is amino } methyl)-2-chloro-5-anisyl] }-4-oxygen-butyl) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 87; 0.18g, 0.17mmol) and triethylamine three hydrofluoride (0.08mL, 0.52mmol), prepare according to the experimental procedure described in example 1, again to prepare reversed-phase HPLC (system 2) purification in addition, and obtain the title compound (50%) of yellow solid.
LRMS(m/z):795(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.35(br.s.,6H)1.71(br.s.,4H)1.92(br.s.,2H)2.06-2.19(c.s,4H)2.38(br.s.,4H)2.65(m.,1H)3.61-3.73(m,4H)4.68(br.s.,1H)5.04(br.s.,1H)5.37(br.s.,1H)6.48(d,J＝9.89Hz,1H)6.87-7.10(c.s.,4H)7.26(br.s.,1H)7.32(d.,J＝5.11H)7.47(d.,J＝5.08,1H)8.13(d,J＝9.89Hz,1H)9.39(s,1H)
Intermedium 88
4-amino-5-fluorine base-2-anisyl nitrile
By uncle-potassium butyrate (6.76g, solution 0.05mol) in anhydrous oxolane (52mL) instills in the mixture of methanol (10.48mL, 0.25mol) and anhydrous oxolane (60mL) in a nitrogen atmosphere in 0 DEG C.Afterwards, in stirred at ambient temperature 10 minutes, then 4-amino-2,5-difluorophenyl nitrile (4g, 0.02mol) is added.Reactant mixture stirs 3 hours in 70 DEG C, by part removal of solvents, then adds ether.Organic layer, with after two carbonate and normal saline washing, dry also to filter, and is under reduced pressure removed by organic solvent, and obtains the title compound (97%) of yellow solid, and it does not need to be further purified and for lower step.
LRMS(m/z):167(M+1) +
Intermedium 89
4-amino-5-fluorine base-2-methoxy benzoic acid
The sodium hydroxide (27.9mL, 0.22mol) of 8M is added 4-amino-5-fluorine base-2-anisyl nitrile (intermedium 88; 5.3g, 0.03mol) solution in ethanol (20mL), mixture is put into hermetic container and is heated to 110 DEG C, and maintains 20 hours.Afterwards, solvent is under reduced pressure removed, and gained coarse fodder is separated between water and ether.Aqueous layer until pH4 with the hydrochloric acid of 6N, then is quenched by ethyl acetate and is got coarse fodder.Dry, filtration also vapourisation under reduced pressure afterwards, and obtain the title compound (80%) of yellow solid, it does not need to be further purified, and for lower step.
LRMS(m/z):186(M+1) +
Intermedium 90
Ethyl 4-amino-5-fluorine base-2-methoxy benzoic acid salt
By 4-amino-5-fluorine base-2-methoxy benzoic acid (intermedium 89; 4.78g, 0.025mol) and at the 1.25M chloride of ethanol (153mL, 0.19mol), prepare according to experimental procedure described in intermedium 37, and obtaining the title compound (91%) of brown solid, it can be used for lower step and does not need to be further purified.
LRMS(m/z):214(M+1) +
Intermedium 91
(4-amino-5-fluorine base-2-anisyl) methanol
By ethyl 4-amino-5-fluorine base-2-methoxy benzoic acid salt (intermedium 90; 0.3g, 1.41mmol) and Li-Al hydrogen compound (69mg, 1.83mmol), prepare according to the experimental procedure described in intermedium 38, and obtaining the title compound (56%) of brown solid, it does not need to be further purified and for lower step.
LRMS(m/z):172(M+1) +
Intermedium 92
[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl) fluorine-based-5-anisyl of-2-] amine
Dimethyl aminopyridine (0.1g, 0.81mmol) and triethylamine (3.4mL, 24.3mmol) are added (4-amino-5-fluorine base-2-anisyl) methanol (intermedium 91; 1.49g, 8.7mmol) solution in oxolane (117mL), be then cooled to 0 DEG C, and add tert-butyl chloro dimethylamino silane (2.45g, 16.2mmol) under an argon atmosphere.Mixture was in stirred at ambient temperature 2 hours, and solvent is under reduced pressure removed, gained coarse fodder with the capable column chromatography of silica gel, with hexane/ether (by 0% to 100%) washing, in addition purification, and obtain the title compound (82%) of light orange solid.
LRMS(m/z):286(M+1) +
Intermedium 93
N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl) fluorine-based-5-anisyl of-2-]-acrylamide
By [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl) fluorine-based-5-anisyl of-2-] amine (intermedium 92; 0.5g; 1.75mmol), acryloyl group chloride (0.174g; 1.93mmol) and diisopropylethylamine (0.45mL; 2.63mmol); prepare according to the experimental procedure described in intermedium 40; gained coarse fodder, with the capable column chromatography of silica gel, with hexane/ether (by 0% to 100%) washing, and obtains the title compound (88%) of white solid.
LRMS(m/z):340(M+1) +
Intermedium 94
Trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl) fluorine-based-5-anisyl of-2-]-amino }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl) fluorine-based-5-anisyl of-2-]-acrylamide (intermedium 93; 576mg, 1.67mmol) and trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 455mg, 1.29mmol), prepare according to the experimental procedure described in intermedium 80, gained coarse fodder recycle silicon glue carries out column chromatography, by hexane/chloroform: methanol (15:1) (by 0% to 100%) washs, in addition purification and obtain the title compound (28%) of solid.
LRMS(m/z):691(M+1) +
Intermedium 95
Trans-4-[(3-{ [fluorine-based-4-of 2-(methylol)-5-anisyl] is amino }-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl) fluorine-based-5-anisyl of-2-]-amino }-3-oxygen propyl group) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 94; 303mg, 0.44mmol) and hydrochloric acid 1M (1.32mL, 1.32mmol), prepare according to the experimental procedure described in intermedium 42, gained coarse fodder silica gel carries out column chromatography, with chloroform/methanol (15/1) washing, in addition purification and obtain the title compound (94%) of oily.
LRMS(m/z):577(M+1) +
Intermedium 96
Trans-4-[{ 3-[(fluorine-based-4-formoxyl of 2--5-anisyl) is amino]-3-oxygen propyl group }-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(4-{ [2-chloro-4-(hydroxymethyl)-5-anisyl] amino }-4-oxygen-butyl)-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 85; 439mg, 0.76mmol) and manganese oxide (IV) (700mg, 8.05mmol), prepare according to the experimental procedure described in intermedium 43, and obtain the title compound (88%) of oily.
LRMS(m/z):577(M+1) +
Intermedium 97
Trans-4-[(3-{ [4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino ethyl) fluorine-based-5-anisyl of-2-] amino-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[(fluorine-based-4-formoxyl of 2--5-anisyl) is amino]-3-oxygen propyl group }-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 96; 392mg, 0.68mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (339mg, 0.86mmol) and triacetyl oxygen sodium borohydride (547mg, 2.46mmol), prepare according to the experimental procedure described in intermedium 30, carry out purification with preparing reversed-phase HPLC (system 2) again, and obtain the title compound (57%) of oily.
LRMS(m/z):894(M+1) +
Example 16
Trans-4-[(3-{ [fluorine-based-4-of 2-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2--dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino }-3-oxygen propyl group) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
Amino by trans-4-[(3-{ [4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl) fluorine-based-5-anisyl of-2-] }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 97; 350mg, 0.39mmol) and triethylamine three hydrofluoride (568mg, 3.53mmol), prepare according to the experimental procedure described in example 1, then obtain the title compound (52%) of white solid with preparing reversed-phase HPLC (system 2) to carry out purification.
LRMS(m/z):779(M+1) +
1H NMR(300MHz,DMSO-d 6)ppm 1.40(br.s.,4H)1.74(br.s.,2H)1.93(br.s.,2H)2.21(s,3H)2.44-2.50(m,1H)2.60-2.74(br.s.,4H)3.62-3.68(m,5H)4.69(br.s.,1H)5.01(br.s.,1H)6.47(d,J＝9.89Hz,1H)6.89(d,J＝9.10Hz,1H)6.97(dd,J＝5.08,3.71Hz,2H)7.01-7.08(c.s.,2H)7.14(d,J＝12.0Hz,1H)7.46(d,J＝6.02Hz,1H)7.73(d,J＝6.0Hz,1H)8.12(d,J＝9.00Hz,1H)10.46(s,1H)
Intermedium 98
(4-amino-2-anisyl) methanol
By methyl 4-amino-2-methoxy benzoic acid salt (2g, 11.04mmol) and lithium aluminum chloride (22.08mL, 22.08mmol), prepare according to the experimental procedure described in intermedium 38, and obtain the title compound (66%) of brown oil, it does not need to be further purified, and for lower step.
LRMS(m/z):154(M+1) +
Intermedium 99
[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-3-anisyl] amine
By (4-amino-2-anisyl) methanol (intermedium 98; 3.2g, 21.35mmol), dimethyl aminopyridine (0.26g, 2.13mmol), triethylamine (5.9mL, 42.7mmol) and uncle-Ding chlorodimethylsilane (4.83g, 32.05mmol), prepare according to the experimental procedure described in intermedium 92, and obtain the title compound (70%) of oily, it does not need to be further purified, and for lower step.
LRMS(m/z):268(M+1) +
Intermedium 100
N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-3-anisyl] acrylamide
By [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-3-anisyl] amine (intermedium 99; 5g, 18.7mmol), acrylic acid chloride (1.98mL, 24.28mmol) and diethyl isopropyl amine (4.9mL, 28.06mmol), prepare according to the experimental procedure described in intermedium 40, and obtain the title compound (63%) of solid.
LRMS(m/z):322(M+1) +
Intermedium 101
Trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-3-anisyl] is amino }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-3-anisyl] acrylamide (intermedium 100; 1.98g, 0.01mol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 1.8g, 0.01mmol), prepare according to the experimental procedure described in intermedium 80, gained coarse fodder recycle silicon glue carries out column chromatography, with chloroform/methanol (50:1) washing, in addition purification, and obtain the title compound (29%) of oily.
LRMS(m/z):673(M+1) +
Intermedium 102
Trans-4-[(3-{ [4-(hydroxymethyl)-3-anisyl] is amino }-3-oxygen propyl group) (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-3-anisyl] amino }-3-oxygen propyl group) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 101; 1g, 1.49mmol) and 1M hydrochloric acid (4.46mL, 4.46mmol), prepare according to the experimental procedure described in intermedium 42, and obtain the title compound (52%) of solid, it does not need to be further purified, and for lower step.
LRMS(m/z):559(M+1) +
Intermedium 103
Trans-4-[{ 3-[(4-formoxyl-3-anisyl) is amino]-3-oxygen propyl group } (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(3-{ [4-(hydroxymethyl)-3-anisyl] amino }-3-oxygen propyl group) (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 102; 0.4g, 0.74mol) and manganese oxide (IV) (0.6g, 7.42mol), prepare according to the experimental procedure described in intermedium 102, and obtaining foamed title compound (72%), it does not need to be further purified and for lower step.
LRMS(m/z):557(M+1) +
Intermedium 104
Trans-4-[(3-{ [4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-3-anisyl] amino-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[(4-formoxyl-3-anisyl) is amino]-3-oxygen propyl group } (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 103; 300mg, 0.54mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (225mg, 0.67mmol) and triacetyl oxygen sodium borohydride (411mg, 1.94mmol), prepare according to the experimental procedure described in intermedium 30, and obtain foamed title compound (76%), it does not need to be further purified, and for lower step.
LRMS(m/z):874(M+1) +
Example 17
Trans-4-[(3-{ [4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-3-anisyl] is amino }-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2)
Amino by trans-4-[(3-{ [4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-3-anisyl] }-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 104; 400mg, 0.46mmol) and triethylamine three hydrofluoride (0.29mL, 1.84mmol), prepare according to the experimental procedure described in example 1, then flood with acetonitrile, and obtain the title compound (27%) of solid.
LRMS(m/z):761(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.42(br.s.,4H)1.76(br.s.,2H)1.96(br.s.,2H)2.24(s,3H)2.45-2.50(m,1H)2.59(br.s.,2H)2.75(br.s.,4H)3.61-3.80(m,5H)4.74(br.s.,1H)5.11(br.s.,1H)6.52(d,J＝9.89Hz,1H)6.90-6.98(m,2H)7.01(dd,J＝5.08,3.71Hz,2H)7.07(c.s.,3H)7.21(m,1H)7.30(s,2H)7.38(s.,1H)7.50(s,1H)8.13(d,J＝9.89Hz,1H)10.10(s,1H)
Intermedium 105
Amino-2, the 5-difluorobenzene hydrochlorates of ethyl 4-
73% sulphuric acid (52.2mL) is added the solution of 4-amino-2,5-difluorophenyl nitrile (6.21g, 38.28mmol) in dioxanes (32.5mL), then stir 4 days in 80 DEG C.Afterwards, water (250mL) is added, and with sodium hydroxide 32% (220mL) alkalization until alkaline pH.Mixture methene chloride rinses.Water-soluble liquid phase is neutralized, and quenches with ethyl acetate and get.Gained organic facies is with normal saline washing, drier and filtration.Under reduced pressure, by removal of solvents, and obtain the title compound (42%) of white solid, it does not need to be further purified and for lower step.
LRMS(m/z):174(M+1) +
Intermedium 106
Amino-2, the 5-difluorobenzene hydrochlorates of ethyl 4-
By amino-2, the 5-difluorobenzene hydrochlorate (intermediums 105 of ethyl 4-; 2.7g, 15.18mmol) and 1.25M hydrochloride in ethanol (52.2mL, 113.7mmol), prepare according to the experimental procedure described in intermedium 37, and obtaining the title compound (92%) of white solid, it does not need further process and for lower step.
LRMS(m/z):202(M+1) +
Intermedium 107
(amino-2, the 5-difluorophenyls of 4-) methanol
By amino-2, the 5-difluorobenzene hydrochlorate (intermediums 106 of ethyl 4-; 2.89g, 13.96mmol) and Li-Al hydrogen compound (26.5mL, 26.5mmol), prepare according to the experimental procedure described in intermedium 38, and obtaining the title compound (98%) of orange solid, it does not need to be further purified and for lower step.
LRMS(m/z):160(M+1) +
Intermedium 108
[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2,5-difluorophenyls] amine
By (amino-2, the 5-difluorophenyls of 4-) methanol (intermedium 107; 2.48g, 15.16mmol), dimethyl aminopyridine (0.18g, 1.47mmol), triethylamine (6.3mL, 15.4mmol) and uncle-Ding chloromethyl silane (4.5g, 30.2mmol) prepare according to the experimental procedure described in intermedium 92, recycle silicon glue carries out column chromatography, with hexane/ethyl acetate washing, and obtains the title compound (85%) of solid.
LRMS(m/z):274(M+1) +
Intermedium 109
N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2,5-difluorophenyls] amine
By [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2,5-difluorophenyls] amine (intermedium 108; 1g, 3.49mmol), acryloyl chloride compound (0.36mL, 4.25mmol) and diisopropyl ethylamino (0.92mL, 5.25mL), prepare according to the experimental procedure described in intermedium 40, recycle silicon glue carries out column chromatography, washs with hexane/ethyl acetate, purification in addition, and obtain the title compound (99%) of solid.
LRMS(m/z):328(M+1) +
Intermedium 110
Trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2,5-difluorophenyls] is amino }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2,5-difluorophenyls] amine (intermedium 109; 0.51g, 1.58mmol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.5g, 1.42mmol), prepare according to the experimental procedure described in intermedium 80, recycle silicon glue carries out column chromatography, with chloroform/hexane (15:1) washing, in addition purification, and obtain the title compound (49%) of yellow oily.
LRMS(m/z):679(M+1) +
Intermedium 111
Trans-4-[(3-{ [the fluoro-4-of 2,5-bis-(hydroxymethyl) phenyl] is amino }-3-oxygen propyl group) (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2,5-difluorophenyls] amino }-3-oxygen propyl group) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 110; 0.5g, 0.75mmol) and 1M hydrochloric acid (2.25mL, 2.25mol), prepare according to the experimental procedure described in intermedium 42, recycle silicon glue carries out column chromatography, with chloroform/methanol (5:1) washing, in addition purification, and obtain the title compound (70%) of white solid.
LRMS(m/z):565(M+1) +
Intermedium 112
Trans-4-[{ 3-[(the fluoro-4-Fonnylphenyl of 2,5-bis-) is amino]-3-oxygen propyl group } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(3-{ [the fluoro-4-of 2,5-bis-(hydroxymethyl) phenyl] amino }-3-oxygen propyl group) (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 111; 0.28g, 0.5mmol) and manganese oxide (IV) (0.54g, 5.32mmol) prepare according to the experimental procedure described in intermedium 43, and the title compound (98%) of oily, it does not need process further and for lower step.
LRMS(m/z):563(M+1) +
Intermedium 113
Trans-4-[(3-{ [4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2,5-difluorophenyls] amino-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[(the fluoro-4-Fonnylphenyl of 2,5-bis-) is amino]-3-oxygen propyl group } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 112; 0.28g, 0.5mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (0.24g, 0.63mmol) and triacetyl oxygen sodium borohydride (0.39g, 1.78mmol), prepare according to the experimental procedure described in intermedium 30, and carry out column chromatography with silica gel, wash with chloroform/methanol (9:1), purification in addition, and obtain the title compound (71%) of oily.
LRMS(m/z):882(M+1) +
Example 18
Trans-4-[(3-{ [2, the fluoro-4-of 5-bis-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] amino-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2).
By trans-4-[(3-{ [4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2,5-difluorophenyls] amino-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 113; 0.3g, 0.35mmol) and triethylamine three hydrofluoride (0.25mL, 1.52mmol), prepare according to the experimental procedure described in example 1, and obtain the title compound (88%) of white solid, it does not need further process.
LRMS(m/z):767(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.41(br.s.,4H)1.74(br.s.,2H)1.95(br.s.,2H)2.22(s,3H)2.45-2.50(m,1H)2.67-2.76(c.s.,4H)3.74(m,2H)4.71(br.s.,1H)5.06(br.s.,1H)6.47(d,J＝9.95Hz,1H)6.88-6.93(m,2H)6.98(dd,J＝5.08,3.71Hz,2H)7.06(dd,J＝3.71,1.24Hz,2H)7.32(m,1H)7.46(dd,J＝5.08,1.24Hz,2H)7.94(m,1H)8.14(d,J＝9.89Hz,1H)10.34(s,1H)10.73(s,1H)
Intermedium 114
Ethyl 4-amino-3-fluorobenzene hydrochlorate
By 4-amino-3-fluorobenzene acid (0.9g, 5.8mmol) and 1.25M hydrofluoride in ethanol (35mL), prepare according to the experimental procedure described in intermedium 37, and obtaining the title compound (97%) of buff white solid, it does not need further process and for lower step.
LRMS(m/z):184(M+1) +
Intermedium 115
(4-amino-3-fluorophenyl) methanol
By ethyl 4-amino-3-fluorobenzene hydrochlorate (intermedium 114; 1g, 5.62mmol) and 1M Li-Al hydrogen compound in oxolane (10.68mL, 10.68mmol), prepare according to the experimental procedure described in intermedium 38, and obtaining the title compound (90%) of faint yellow oily, it does not need further process and for lower step.
LRMS(m/z):142(M+1) +
Intermedium 116
[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-fluorophenyl] amine
By (4-amino-3-fluorophenyl) methanol (intermedium 115; 0.8g, 5.72mmol), dimethyl aminopyridine (0.07g, 0.57mmol), triethylamine (2.39mL, 17.17mmol) and tert-butyl chloro dimethylsilane (1.7g, 11.4mmol), prepare according to the experimental procedure described in intermedium 92, recycle silicon glue carries out column chromatography, with hexane/ethyl acetate (4:1) washing, in addition purification, and obtain the title compound (96%) of faint yellow oily.
LRMS(m/z):256(M+1) +
Intermedium 117
N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-fluorophenyl] acrylamide
By [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-fluorophenyl] amine (intermedium 116; 1.6g, 6.52mmol), acryloyl chloride compound (0.58mL, 7.17mmol) and diisopropyl ethylenediamine (1.7mL, 9.77mmol), prepare according to the experimental procedure described in intermedium 40, the capable column chromatography of recycle silicon glue, wash by hexane/ethyl acetate (80:20), thus purification, and obtain the title compound (43%) of white solid.
LRMS(m/z):310(M+1) +
Intermedium 118
Trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-fluorophenyl] is amino }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-fluorophenyl] acrylamide (intermedium 117; 0.5g, 1.62mmol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.51g, 1.46mmol) and triacetyl oxygen sodium borohydride (1.1g, 5.24mmol), prepare according to the experimental procedure described in intermedium 30, again with preparing reversed-phase HPLC (system 2) purification in addition, and obtain title compound (44%).
LRMS(m/z):661(M+1) +
Intermedium 119
Trans-4-[(3-{ [the fluoro-4-of 2-(hydroxymethyl) phenyl] is amino }-3-oxygen propyl group) (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-fluorophenyl] amino }-3-oxygen propyl group) (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 118; 84mg, 0.13mmol) and 1M hydrochloric acid (0.38mL, 0.38mmol), prepare according to the experimental procedure described in intermedium 42, the capable column chromatography of recycle silicon glue, wash with Cl3CH to Cl3CH/MeOH 15:1, thus purification and obtain the title compound (81%) of oily.
LRMS(m/z):310(M+1) +
Intermedium 120
Trans-4-[{ 3-[(the fluoro-4-Fonnylphenyl of 2-) is amino]-3-oxygen propyl group } (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
The intermedium 119 of 325mg (0.59mmol) is dissolved in the Cl3CH of 7.6ml, and in 45 minutes, instills the MnO2 of the activation of 546.8mg (6.29mmol) under an argon atmosphere.System stirs 3 hours in 45 DEG C, filters afterwards, and rinse with Cl3CH, filtrate concentrates in a vacuum, and obtains the pure title compound (88% productive rate) of 290mg.
Intermedium 121
Trans-4-[(3-{ [4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2-fluorophenyl] amino-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[(the fluoro-4-Fonnylphenyl of 2-) is amino]-3-oxygen propyl group } (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate (0.29g, 0.53mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1, 2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (0.26g, 0.67mmol), and triacetyl oxygen sodium borohydride (0.4g, 1.92mmol), prepare according to the experimental procedure described in intermedium 30, carry out purification with preparing reversed-phase HPLC (system 2) and obtain title compound (36%) again.
LRMS(m/z):864(M+1) +
Example 19
Trans-4-[(3-{ [the fluoro-4-of 2-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] is amino }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2).
Amino by trans-4-[(3-{ [4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-2-fluorophenyl] }-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 121; 170mg, 0.2mmol) and triethylamine three hydrofluoride (137mg, 0.85mmol), prepare according to the experimental procedure described in example 1, and obtain the title compound (88%) of white solid, it does not need further process.
LRMS(m/z):749(M+1) +.
1H NMR(300MHz,DMSO-d6)ppm 1.47(br.s.,4H)1.81(br.s.,2H)2.01(br.s.,2H)2.29(s,3H)2.45-2.50(m,1H)2.57(br.s.,2H)2.78(br.s.,4H)3.83(m,2H)4.77(br.s.,1H)5.15(br.s.,1H)6.54(d,J＝9.89Hz,1H)6.94-7.00(m,2H)7.01-7.08(m,2H)7.09-7.19(m 3H)7.25-7.35(m,2H)7.53(d,J＝6.00Hz,1H)8.02(m 1H)8.18(d,J＝9.89Hz,1H)10.47(s,1H)
Intermedium 122
Trans-4-[[3-({ 2-chloro-5-methoxyl-4-[(E)-2-methoxyvinyl] phenyl } is amino)-3-oxygen propyl group] (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By lithium two (TMS) amide (2.43mL of 1M, solution 2.43mmol) in a nitrogen atmosphere, in 0 DEG C of instillation (methoxyl methyl) triphenyl phosphorus chloride (0.83g, suspension 2.43mmol) in anhydrous oxolane (4.3mL), after mixture being stirred 30 minutes, instill trans-4-((3-(2-chloro-4-formoxyl-5-anisidino-)-3-oxygen propyl group) (methyl)-amino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 43; 0.41g, 0.69mmol) solution in anhydrous oxolane (2.1mL).Afterwards, stir 30 minutes in 0 DEG C, then in stirring at room temperature 1.5 hours, gained coarse fodder added saturated ammonium chloride solution, and quench with ethyl acetate and get.Dry after organic layers with water, normal saline washing, and solvent is under reduced pressure removed, and obtains the solid of orange, recycle silicon glue carries out column chromatography, with methine chloride/isopropyl alcohol (93:7) washing, in addition purification, and obtain the title compound (56%) of white solid.
LRMS(m/z):620(M+1) +
Intermedium 123
Trans-4-[(3-{ [2-chloro-5-methoxyl-4-(2-oxygen ethyl) phenyl] is amino }-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By the hydrochloric acid (0.34mL, 0.7mmol) of 2M. instill trans-4-[[3-({ 2-chloro-5-methoxyl-4-[(E)-2-methoxyvinyl] phenyl } is amino)-3-oxygen propyl group] (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 122; 0.36g, 0.17mmol) solution in anhydrous oxolane (0.5mL).Afterwards, stir 5.5 hours in 65 DEG C.The mixture of water/ice is poured into, then quench by ethyl acetate and get, dry after organic layers with water and normal saline washing, and solvent is under reduced pressure removed, gained coarse fodder recycle silicon glue carries out column chromatography, the washing of the following Methochloride/methanol (95:5), in addition purification, and obtain title compound (90%).
LRMS(m/z):606(M+1) +
Intermedium 124
Trans-4-[(3-{ [4-(2-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino ethyl)-2-chloro-5-anisyl] amino-3-oxygen propyl group) methyl] amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1, 2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (78mg, 0.2mmol), diisopropyl ethylenediamine (0.03mL, 0.2mmol), and triacetyl oxygen sodium borohydride (108mg, 0.51mmol) add trans-4-[(3-{ [2-chloro-5-methoxyl-4-(2-oxygen ethyl) phenyl] amino }-3-oxygen propyl group)-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 123, 173mg, 0.16mmol) solution in methanol (1.73mL).Afterwards in stirred at ambient temperature 2.5 hours, in 0 DEG C, mixture is added the bicarbonate of 4% of 20mL, then quench with ethyl acetate and get coarse fodder, afterwards with water and normal saline washing, drying, and solvent is removed in decompression is lower.Gained coarse fodder recycle silicon glue carries out column chromatography, with methine chloride/methanol (9:1) washing, thus purification, and obtain the title compound (52%) of yellow solid.
LRMS(m/z):924(M+1) +
Example 20
Trans-4-[(3-{ [2-chloro-4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl)-5-anisyl] amino-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2)
By trans-4-[(3-{ [4-(2-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl)-2-chloro-5-anisyl] is amino }-3-oxygen propyl group) methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 124; 70mg, 0.08mmol) and triethylamine three hydrofluoride (0.049mL, 0.3mmol), prepare according to the experimental procedure described in example 1, then with acetonitrile dipping, and obtain the title compound (79%) of white solid.
LRMS(m/z):809(M+1) +.
1H NMR(300MHz,DMSO-d6)ppm 1.34(br.s.4H)1.70(b.s 2H)1.88(b.s.2H)2.20(s.3H)2.51(m 1H)2.67(br.s.2H)2.78(br.s.2H)3.26(c.s.3H)3.67(s3H)4.63(m.1H)5.08(br.s.1H)6.45(d,J＝9.89Hz,1H)6.84–6.95(m,3H)7.01-7.08(m,2H)6.99-7.07(m 3H)7.16-7.23(m,2H)7.40(d,J＝6.00Hz,1H)7.71(s 1H)8.12(d,J＝9.89Hz,1H)10.60(s,1H)
Intermedium 125
Trans-4-[(3-{2-chloro-5-methoxyl group-4-[(E)-2-methoxyvinyl] phenoxy group } propyl group) methyl]-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[[3-(2-chloro-4-formoxyl-5-methoxy phenoxy) propyl group] (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 57; 282mg, 0.48mmol), (methoxyl methyl) triphenyl phosphorus chloride (423mg, 1.2mmol) and lithium two (TMS) amide (1.2mL of 1M, 1.2mmol), prepare according to the experimental procedure described in intermedium 122, recycle silicon glue carries out column chromatography, washs purification in addition, and obtain title compound (59%) with ether/methanol (9:1).
LRMS(m/z):607(M+1) +
Intermedium 126
Trans-4-[{ 3-[2-chloro-5-methoxyl group-4-(2-oxygen ethyl) phenoxy group] propyl group } (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[(3-{2-chloro-5-methoxyl group-4-[(E)-2-methoxyvinyl] phenoxy group } propyl group) methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 125; 193mg, 0.28mmol) and 2N hydrochloric acid (0.42mL, 0.84mmol), prepare according to the experimental procedure described in intermedium 123, recycle silicon glue carries out column chromatography, with methine chloride/methanol (95:5) washing, in addition purification, and obtain title compound (81%).
LRMS(m/z):593(M+1) +
Intermedium 127
Trans-4-[3-[4-(2-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino ethyl)-2-chloro-5-methoxy phenoxy] propyl group-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 3-[2-chloro-5-methoxyl group-4-(2-oxygen ethyl) phenoxy group] propyl group } (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 126, 137mg, 0.23mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1, 2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (109mg, 0.28mmol), diisopropyl ethylenediamine (0.048mL, 0.28mmol), and triacetyl oxygen sodium borohydride (103mg, 0.46mmol), prepare according to the experimental procedure in intermedium 124, purification is carried out again with preparing reversed-phase HPLC (system 2), and obtain the title compound (40%) of oily.
LRMS(m/z):911(M+1) +
Example 21
Trans-4-[3-[the chloro-4-of 2-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl)-5-methoxy phenoxy] propyl group } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2)
By trans-4-[{ 3-[4-(2-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl)-2-chloro-5-methoxy phenoxy] propyl group }-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 127; 83mg, 0.09mmol) and triethylamine three hydrofluoride (0.06mL, 0.4mmol), prepare according to the experimental procedure described in example 1, then flood with acetonitrile, and obtain the title compound (77%) of white solid.
LRMS(m/z):796(M+1) +.
1H NMR(300MHz,DMSO-d6)ppm 1.41(m.,4H)1.76(br.s.,2H)1.87(br.s.,2H)1.94(br.s.,2H)2.23(s,3H)2.44(br.s.,2H)2.50(br.s.,1H)2.61(m.,2H)2.78(br.s.,3H)2.92(br.s.,4H)3.84(s.,3H)4.13(br.s.,2H)4.72(br.s.,1H)5.23(br.s.,1H)6.56(d,J＝9.89Hz,1H)6.77(s.,1H)6.94-7.04(m,3H)7.10-7.17(m,3H)7.22(s.,1H)7.31(br.s.,1H)7.50(d,J＝9.89Hz,1H)8.24(s,1H)
Intermedium 128
Methyl 4-amino-5-iodo-2-methoxy benzoic acid salt
By solution instillation methyl 4-amino-2-methoxy benzoic acid salt (13g, the 0.07mol) solution in acetic acid (300mL) of monochlorinated iodine (11.5g, 0.07mol) in acetic acid (50mL).Afterwards in stirred at ambient temperature 1.5 hours, precipitate is leached, and with washed with ether.Dissolve with the bicarbonate of 4%, and quench with ethyl acetate and get, organic layer is with dry after normal saline washing, and solvent is removed in decompression is lower, obtains the title compound (88%) of white solid.
LRMS(m/z):308(M+1) +
Intermedium 129
Methyl 4-amino-5-cyano-2-methoxy benzoic acid salt
By the methyl 4-amino-5-iodo-2-methoxy benzoic acid salt (intermedium 128 in slenck container; 5g, 16.28mmol) and the solution of two zinc cyanides (1.5g, 12.77mmol) in dimethyl formamide (50mL), remove air with nitrogen.Then add quadruple (tetrakis; 1g, 0.87mmol), and to stir 2 hours in 80 DEG C, then add water, and quench with ethyl acetate and get coarse fodder, organic layer is with normal saline washing, drying, and solvent is under reduced pressure removed.Gained coarse fodder with methanol and ether process, and obtains the title compound (76%) of yellow solid.
LRMS(m/z):207(M+1) +
Intermedium 130
2-amino-5-(hydroxymethyl)-4-anisyl nitrile
The lithium tetrahydroborate (21.7mL, 43.4mmol) of 2M is instilled methyl 4-amino-5-cyano-2-methoxy benzoic acid salt (intermedium 129 in a hydrogen atmosphere in 0 DEG C; 0.59g, 2.88mmol) solution in oxolane (40mL), instill ethanol (7.5mL) after 5 minutes again.Coarse fodder, in stirred at ambient temperature 5 days, is poured in the saturated solution of ammonium chloride and ice, and is stirred 10 minutes by mixture afterwards, then quenches with ethyl acetate and get coarse fodder, and with water and normal saline washing, drying, and solvent is removed in decompression is lower.The title compound (81%) of the white solid obtained.
LRMS(m/z):179(M+1) +
Intermedium 131
2-amino-5-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-4-anisyl nitrile
By 2-amino-5-(hydroxymethyl)-4-anisyl nitrile (intermedium 130; 0.44g, 2.35mmol), tert-butyl chlorodimethylsilane (0.71g, 4.71mmol) and imidazoles (0.48g, 7.05mmol), prepare according to the experimental procedure described in intermedium 39, and obtaining the title compound (79%) of white solid, it does not need further process and for lower step.
LRMS(m/z)：293(M+1) +
Intermedium 132
5-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-isocyano group-4-anisyl nitrile
By 2-amino-5-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-4-anisyl nitrile (intermedium 131; 0.64g, 1.87mmol), triphosgene (0.21g, 0.69mmol) and triethylamine (0.52mL, 3.73mmol), prepare according to the experimental procedure described in intermedium 59, and the title compound (56%) of yellow solid, it does not need process further and for lower step.
LRMS(m/z):319(M+1) +
Intermedium 133
Trans-4-[{ 2-[({ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-cyano group-5-methoxy-phenyl] is amino } carbonyl) oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By 5-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-isocyano group-4-anisyl nitrile (intermedium 132; 0.48g, 1.51mmol), trans-4-(methylamino) cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 5; 0.44g, 1.13mmol) and diisopropyl ethylenediamine (0.6mL, 3.44mmol), prepare according to the experimental procedure described in intermedium 61, the capable column chromatography of recycle silicon glue, with methine chloride/isopropyl alcohol (9:1) washing, in addition purification, and obtain the title compound (14%) of yellow solid.
LRMS(m/z):714(M+1) +
Intermedium 134
Trans-4-[{ 2-[({ [2-cyano group-4-(hydroxymethyl)-5-anisyl] is amino } carbonyl)-oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 2-[({ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-cyano group-5-methoxy-phenyl] is amino } carbonyl) oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 133; 155mg; 0.17mmol) and 1M hydrochloric acid (0.65mL, 0.65mmol), prepare according to the experimental procedure described in intermedium 42, recycle silicon glue carries out column chromatography, the following Methochloride/isopropyl alcohol (9:1) washing, purification in addition, and obtain foamed title compound (72%).
LRMS(m/z):600(M+1) +
Intermedium 135
Trans-4-[[2-({ [(2-cyano group-4-formoxyl-5-anisyl) is amino] carbonyl } oxygen base) ethyl]-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 2-[({ [2-cyano group-4-(hydroxymethyl)-5-anisyl] is amino } carbonyl)-oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 134; 68mg, 0.11mmol) and manganese oxide (IV) (106mg, 1.22mmol), prepare according to the experimental procedure described in intermedium 43, and obtaining the title compound (94%) of yellow foam, it does not need further process and for lower step.
LRMS(m/z):598(M+1) +
Intermedium 136
Trans-4-[2-[([4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2-cyano group-5-toloxyl] amino-carbonyl) oxygen base] ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[[2-({ [(2-cyano group-4-formoxyl-5-anisyl) is amino] carbonyl } oxygen base) ethyl]-(methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 135; 62mg, 0.1mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (50mg, 0.13mmol), diisopropyl ethylenediamine (0.02mL, 0.14mmol) and triacetyl oxygen boron hydride (70mg, 0.33mmol), prepare according to the experimental procedure described in intermedium 135, and obtain foamed title compound (77%).
LRMS(m/z):917(M+1) +
Example 22
Trans-4-[{ 2-[({ [2-cyano group-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl)-oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2)
By trans-4-[{ 2-[({ [4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-2-cyano group-5-toloxyl] is amino }-carbonyl) oxygen base] ethyl } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 136; 75mg, 0.08mmol) and triethylamine three hydrofluoride (0.05mL, 0.31mmol), prepare according to the experimental procedure described in example 1, then flood with acetonitrile, and obtain the title compound (79%) of white solid.
LRMS(m/z):802(M+1) +.
1H NMR(300MHz,DMSO-d6)ppm 1.37(br.s.,4H)；1.73(m.,2H)；1.91(m.,2H)；2,22(s.,3H)；2.43(b.s.,1H)；2.66(m.,2H)；2.73(m.,2H)；3.76(m.,2H)；3.81(s.,3H)；4.12(m.,2H)；4.69(b.s.,1H)；5.10(m.,1H)；6.50(d.,J＝12Hz,1H)；6.89-7.01(m.,3H)；7.06(m.,3H)；7.13(s.,1H)；7.25(b.s.,1H)；7.46(d.,J＝6Hz；1H)；7.68(s.,1H)；8.13(d.,J＝12Hz,1H)；9.71(s.,1H)；10.37(b.s.,1H).
Intermedium 137
Amino-2, the 5-difluoro benzoic acids of 4-
The 73%p/p sulphuric acid of 52.2mL is joined the solution of 4-amino-2,5-difluorophenyl nitrile (6.21g, 38.28mmol) in dioxanes (32.5mL), then stir 96 hours at 80 DEG C.The water of 250mL poured into by coarse fodder, and with 32% sodium hydroxide by it alkalization, until alkaline pH.Then rinse with methine chloride.The hydrochloric acid neutralization of water-soluble liquid phase 5N, then get coarse fodder and drying by ethyl acetate essence.Solvent is under reduced pressure removed, and obtains the title compound (42%) of white solid, and it does not need to be further purified, and for lower step.
LRMS(m/z):174(M+1) +
Intermedium 138
Amino-2, the 5-difluorobenzene hydrochlorates of ethyl 4-
By amino for 4-in hydrogen chloride (1.25mL)-2,5-difluoro benzoic acid (intermediums 137; 2.7g; Solution 0.015mol) in ethanol (91mL, 0.113mol) stirs 24 hours in 60 DEG C.Afterwards, solvent is under reduced pressure removed, gained coarse fodder water and solid two processes of carbonate treatment, obtains the pH of alkalescence.Stir after a few minutes, get by ethyl acetate essence, organic layer washed with brine rinses and dry, and solvent is removed in decompression is lower, obtains the title compound (92%) of white solid, and it does not need to be further purified and for lower step.
LRMS(m/z):202(M+1) +
Intermedium 139
(amino-2, the 5-difluorophenyls of 4-) methanol
By amino-2, the 5-difluorobenzene hydrochlorate (intermediums 138 of ethyl 4-; 2.89g, 0.013mol) and Li-Al hydrogen compound (26.5mL, 0.02mol), prepare according to the experimental procedure described in intermedium 38, and obtaining the title compound (98%) of orange solid, it does not need further process and for lower step.
LRMS(m/z):160(M+1) +
Intermedium 140
[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2,5-difluorophenyls] amine
By (amino-2, the 5-difluorophenyls of 4-) methanol (intermedium 139; 2.48g, 0.01mol), dimethyl aminopyridine (0.18g, 0.001mmol), triethylamine (6.3mL, 0.04mmol) and tert-butyl chlorine dimethylamino silane (4.56g, 0.03mmol) prepare, recycle silicon glue carries out column chromatography, washs by hexane/ethyl acetate, purification in addition, and obtain the title compound (85%) of solid.
LRMS(m/z):274(M+1) +
Intermedium 141
Tert-butyl [(the fluoro-4-isocyanatophenyl of 2,5-bis-) oxygen base] dimethylamino silane
By [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2,5-difluorophenyls] amine (intermedium 140; 0.4g, 1.46mmol), triphosgene (0.15g, 0.53mmol) and triethylamine (0.4mL, 2.93mmol), prepare according to the experimental procedure described in intermedium 59, and obtaining the title compound (99%) of oily, it does not need further process and for lower step.
LRMS(m/z):300(M+1) +
Intermedium 142
Trans-4-[2-[([4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2,5-difluorophenyls]-amino carbonyl) oxygen base] ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By tert-butyl [(the fluoro-4-isocyanatophenyl of 2,5-bis-) oxygen base] dimethylamino silane (intermedium 141; 0.43g, 1.46mmol), trans-4-[(2-ethoxy) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 60; 0.57g, 1.46mmol) and diisopropyl ethylenediamine (0.38mL, 2.22mmol), (response time and temperature: 24 hours is prepared according to the experimental procedure described in intermedium 61,60 DEG C), recycle silicon glue carries out column chromatography, the following Methochloride/ethanol (9:1) washing, purification in addition, and obtain the title compound (41%) of colorless oil.
LRMS(m/z):695(M+1) +
Intermedium 143
Trans-4-[{ 2-[({ [the fluoro-4-of 2,5-bis-(hydroxymethyl) phenyl] is amino } carbonyl) oxygen base]-ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 2-[({ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2,5-difluorophenyls]-amino } carbonyl) oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 142; 0.42g, 0.61mmol) and 1M hydrochloric acid (1.83mL, 1.83mmol), prepare according to the experimental procedure described in intermedium 42, recycle silicon glue carries out column chromatography, with methine chloride/ethanol (9:1) washing, thus purification, and obtain the title compound (98%) of white solid.
LRMS(m/z):581(M+1) +
Intermedium 144
Trans-4-[[2-({ [(the fluoro-4-Fonnylphenyl of 2,5-bis-) is amino] carbonyl } oxygen base) ethyl] (methyl l)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[{ 2-[({ [the fluoro-4-of 2,5-bis-(hydroxymethyl) phenyl] is amino } carbonyl) oxygen base]-ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 143; 0.35g, 0.6mmol) and manganese oxide (IV) (0.57g, 6.6mmol), prepare according to the experimental procedure described in intermedium 43, and obtaining the title compound (87%) of colorless oil, it does not need further process and for lower step.
LRMS(m/z):579(M+1) +
Intermedium 145
Trans-4-[2-[([4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2,5-difluorophenyls] amino carbonyl)-oxygen base] ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By trans-4-[[2-({ [(the fluoro-4-Fonnylphenyl of 2,5-bis-) is amino] carbonyl } oxygen base) ethyl] (methyl l)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 144, 0.3g, 0.52mmol), (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1, 2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) (0.24g, 0.62mmol), diisopropyl ethylenediamine (0.1mL, 0.62mmol), and triacetyl oxygen sodium borohydride (0.23g, 1.04mmol), prepare according to the experimental procedure described in intermedium 124, purification is carried out again to prepare reversed-phase HPLC (system 2), and obtain the title compound (63%) of colorless oil.
LRMS(m/z):898(M+1) +
Example 23
Trans-4-[{ 2-[({ [2, the fluoro-4-of 5-bis-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] amino carbonyl) oxygen base] ethyl (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2)
By trans-4-[{ 2-[({ [4-({ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2,5-difluorophenyls] amino carbonyl)-oxygen base] ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate (intermedium 145; 0.29g, 0.32mmol) and triethylamine three hydrofluoride (0.22mL, 1.39mmol), prepare according to the experimental procedure described in example 1, gained coarse fodder floods with acetonitrile, and obtains the title compound (81%) of white solid.
LRMS(m/z):783(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.37(m.,4H)；1.71(m.,2H)；1.92(m.,2H)；2,21(s.,3H)；2.42(b.s.,1H)；2.66(m.,4H)；3.72(m.,2H)；4.11(m.,2H)；4.69(b.s.,1H)；5.05(m.,1H)；6.47(d.,J＝12Hz,1H)；6.88-6.93(m.,1H)；6.97(m.,2H)；7.09(m.,3H)；7.25(m.,2H)；7.46(d.,J＝6Hz；2H)；8.14(d.,J＝12Hz,1H)；9.50(s.,1H)；10.35(b.s.,1H).
Intermedium 146
2,2-dimethylbutyl-3-olefin(e) acid
The diethylamine of 2.11ml (20.31mmoI) is dissolved in the THF of 9ml in Schlenck container.After being cooled to-78 DEG C, add the n-butyl lithium of 8.60ml (21.5mmol).This solution stirs 15 minutes in 0 DEG C.System is cooled to-78 DEG C again, then instills the solution of it (E)-2-methyl butyl-2-olefin(e) acid of 1.0g (9.69mmol) in 9mlTHF.Yellow solution stirs 30 minutes in 0 DEG C, then is cooled to, by after 78 DEG C, slowly instill the solution of Dimethylsulfate in 22ml THF of 0.92ml.System stirs 30 minutes in-78 DEG C, then in stirring at room temperature 1 hour, then add extra water, and rinse three times with Anaesthetie Ether.Aqueous layer with dense hydrochloric acid in 0 DEG C, and is quenched by ethyl acetate and is got three times.Organic facies then with normal saline washing, drying concentrated, and obtains title compound, and its purity is enough for lower step.
Intermedium 147
N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-2,2-dimethylbutyl-3-alkene amide
By 2 of 0.87g (7.62mmol), 2-dimethylbutyl-3-olefin(e) acid is dissolved in the sulfurous acid chloride of 1.79ml (24.51mmol), and stir 4 hours in 100 DEG C, unnecessary thionyl chloride is evaporated, residue is then dissolved in the THF of 28ml, and slowly adds intermedium 39 (2.1g in-20 DEG C; 6.12mmol) and the solution of triethylamine in 32ml THF of 1.71ml (12.27mmol).System stirs 20 minutes in-20 DEG C, then stirring at room temperature whole evening.Coarse fodder is poured into the solution of 4% sodium bicarbonate of 75ml, and quench with the ethyl acetate of 75ml and get compound, more concentrated with water rinsing, drying, and obtain the grease (there is the target compound of intermedium 39) of 2.42g.Again through SP1 chromatography purification (hexane is to isohexane ethyl acetate 8:2), and obtain the pure title compound (37% productive rate) of the colorless oil of 0.89g.
Intermedium 148
N-[4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-2,2-dimethyl-3-oxygen propionic acid amide .s
The intermedium 147 of 0.95g (2.39mmol) is dissolved in the THF of 19ml, then under argon gas atmosphere, adds the N-methylmorpholine N-oxide of 0.56g (4.78mmol) and the 4%OsO4 aqueous solution of 0.73ml (0.18mmol).System stirs whole evening at 30 DEG C, then adds the OsO4 solution of 0.36ml, and stirs 6 hours.Solvent is removed under vacuum, and residue is then suspended in the water of 100ml, then gets with the ether ethyl ester essence of 100ml.Organic facies is with normal saline washing, drying concentrated, and residue (brown solid corresponding to the 1.08g of intermedium glycol) is then suspended in the water of THF and 1.3ml of 8.2ml.Add the sodium metaperiodate of 0.77g (3.59mmol), system is stirred at ambient temperature whole evening, and solvent is removed under vacuum, and residue is suspended in the sodium bicarbonate of 4%, quenches get with the ether ethyl ester of 2x50ml.Organic layer is concentrated with water rinsing, drying, and obtains the dark oil (45% title compound, and the derivant of 55% desilylation) of 0.89g, and it can be used for lower step.
Intermedium 149
Trans-4-[(3-{ [4-({ [tert-butyl (dimethyl) silicyl] oxygen base } methyl)-2-chloro-5-anisyl]-amino }-2,2-dimethyl-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
Be dissolved in the THF of 12.6ml by the intermedium 148 of 0.63g (1.58mmol), then add the intermedium 5 of 0.69g (1.96mmol) and the acetic acid of 0.225ml, system stirs whole evening at 65 DEG C.With ice bath by after external refrigeration, add the SODIUM CYANO BOROHYDRIDE of 1.08g (5.11mmol), and stir 15 minutes in 5 DEG C, then in stirring at room temperature 45 minutes.Solution is poured into the sodium bicarbonate solution of 4% of 50ml, and get with the ethyl acetate essence of 3x30ml.Organic facies with sodium bicarbonate solution and normal saline washing, drying concentrated, and obtains the brown oil (title compound containing 7% and 6% complexity being equivalent to the derivant of desilylation mix thing) of 1.0g, and it can be used for lower step.
Intermedium 150
Trans-4-[(3-{ [2-chloro-4-(hydroxymethyl)-5-anisyl] is amino }-2,2-dimethyl-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
The solution of complex mixture in 20.1ml THF of the intermedium 149 of 1.0g is cooled to 5 DEG C, meanwhile, the 1N aqueous hydrochloric acid solution of instillation 0.707ml.System, in stirred at ambient temperature 3 hours, after cooling, adds the water of 40ml, is transferred near 8 by pH with solid NaHCO3.Get with the ethyl acetate essence of 2x30ml again, and with 4% sodium bicarbonate and normal saline washing, drying concentrated.Residue (dark oil containing the 0.88g of 11% title compound) through SP1 device, and washs with CH2Cl2 to Cl2CH2/MeOH 95:5, in addition purification, and obtains the non-pure white solid (HPLC purity is 67%) of 0.104g.
Intermedium 151
Trans-4-[{ 3-[(2-chloro-4-formoxyl-5-anisyl) is amino]-2,2-dimethyl-3-oxo-propyll } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
The intermedium 150 (purity 67%) of 104mg is dissolved in the Cl3CH of 2.08ml, and adds the MnO2 of the activation of 98mg.System stirs whole evening at 45 DEG C, after diatomite filtration, filtrate is concentrated, and obtain the orange grease (64% purity) of 101mg, it can be used for lower step.
Intermedium 152
Trans-4-[(3-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-5-anisyl] amino-2,2-dimethyl-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
The intermedium 151 (64% purity) of 101mg is dissolved in the MeOH of 1ml, then adds 5-((1R)-2-amino-1-{ [tert-butyl (dimethyl) silicyl] oxygen base } ethyl)-8-Hydroxy-quinolin-2 (1H)-one acetate (prepared by the preparation 8 according to US2006003593), the diisopropylethylamine of 0.023ml (0.13mmol) and the triacetyl oxygen sodium borohydride of 72mg (0.34mmol) of 51mg (0.13mmol).System was in stirred at ambient temperature 2.5 hours.The 4%NaHCO3 solution of 25ml poured into by coarse fodder, and get with the ethyl acetate essence of 3x15ml.Organic layer with 4%NaHCO3 solution and normal saline washing, drying concentrated, and the solid of 147mg.Through SP1 system (Cl 2cH 2to Cl 2cH 2/ MeOH 9:1) chromatography purification, obtain the title compound of 96mg.
Example 24
Trans-4-[(3-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-5-anisyl] amino-2,2-dimethyl-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
The intermedium 152 (86% purity HPLC) of 90mg (0.08mmol) is dissolved in the THF of 2.7ml, then adds the Et of 0.054ml (0.33mmol) 3n (HF) 3.System is stirred at ambient temperature whole evening, and solvent is removed under vacuum, and residue is then suspended in the water of 20ml.NaHCO3 solid is added until saturated, then adds normal saline washing, and dry, concentrated.Coarse fodder again to prepare reversed-phase HPLC (system 2) purification, and obtains the title compound (98% purity, 44% productive rate) of colorless solid.
LRMS(m/z):823(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.16(s.,6H)1.36(br.s.,4H)1.76(br.s.,2H)1.94(br.s.,2H)2.27(s,3H)2.48-2.50(m,1H)2.59(br.s.,2H)2.63-2.72(br.s.,2H)3.58-3.64(m,5H)；3.71(s.,3H)4.69(br.s.,1H)5.02(br.s.,1H)6.46(d,J＝9.89Hz,1H)6.86-6.90(m,2H)6.97(dd,J＝5.08,3.71Hz,2H)7.06(m.,2H)7.30(s,1H)7.46(d.,J＝6Hz,2H)7.91(s,1H)8.13(d,J＝9.89Hz,1H)10.53(s,1H)
Intermedium 153
5-chloro-4-hydroxyl-2-methoxy benzoic acid methyl ester
HBF4 (16.2mL, 48% aqueous solution) is added the suspension of 4-amino-5-chloro-2-methoxy benzoic acid in 50ml H2O of 10g (48mmol).White cake block is cooled to 0 DEG C, then instills (through funnel, 10 minutes) NaNO2 (3.76g is in the H2O of 30mL), suspension becomes faint yellow, stirs 30 minutes.Collect white precipitate after filtration, separating heavy nitrogen salt (weight in wet base: 12.97g).Diazol is suspended in ice AcOH (500mL), and stirs 1 hour (it becomes brown solution) at 100 DEG C.It continues two hours under RT.Solvent is under reduced pressure removed, and brown oil residue is suspended in saline (500mL), and quenches with EtOAC (3x300mL) and get.Combining organic layer is dry, and filter and vapourisation under reduced pressure, resulting brown oil is with the 0.5M NaOH process in MeOH (150mL), and stir 90 minutes under RT, stir 3 hours under RT again, solvent is evaporated, and residue is dissolved in H2O (250mL) again.With 5N HCl by after acidified aqueous solution to pH=2, get with CH2Cl2 (3x250mL) essence, again precipitation solid is leached, with Et2O washing, drying (45 DEG C in stove, 90 minutes), and obtain the dark brown solid of 4.3g, again with Merck post (80g tripoli, road strategic point (family name) head) carry out column chromatography, and use with CH2Cl2 (A) and CH2Cl2/EtOAc 8:2 (B) for detergent (19 column volumes of 0% to 25%B and 25% are to 10CV, the 100mL/min of the 60%B), in addition purification.Collect suitable part, and remove solvent, and obtain the light red solid of 2.9g (27% productive rate).
Intermedium 154
The chloro-4-of 2-(hydroxymethyl)-5-methoxyl group phenol
The intermedium 153 of 1.1g (5.08mmol) is dissolved in the THF of 30ml.Solution is cooled to 0 DEG C, then instills the solution of 1M LiAlh4 in THF of 9.65ml (9.65mmol).System stirs 10 minutes at 0 DEG C, then in stirred at ambient temperature 1 hour, adds the extra hydride solution of 25%, and in stirred at ambient temperature 2 hours, then stir 30 minutes at 45 DEG C.After being cooled to 0 DEG C again, dry, concentrated, and obtain the residue of 930mg.Through chromatography purification (SP1 system is washed with Cl3CH to Cl3CH/MeOH 9:1), finally obtain the pure title compound (46% productive rate) of 459mg.
Intermedium 155
[the chloro-2-anisyl of 4-(4-bromine butoxy)-5-] methanol
The mixture of potassium carbonate in the acetone of 9.2ml of the Isosorbide-5-Nitrae-dibromobutane of the intermedium 154 of 391mg (2.04mmol), 1.48ml (12.27mmol) and 577mg (4.09mmol) is heated to 75 DEG C under Ar atmosphere in microwave oven.After filtration, filtrate concentrated, residue is chromatography purification (SP1 system is washed to hexane/EtOAc 1:1 with hexane) then, and obtains 264mg (39% productive rate).
Intermedium 156
Trans-4-[{ 4-[the chloro-4-of 2-(hydroxymethyl)-5-methoxy phenoxy] butyl } (methyl) is amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate
By the intermedium 5 of the intermedium 155 of 230mg (0.71mmol), 256mg (0.71mmol) and the triethylamine of 0.19ml (1.4mmol), solution in the THF of MeCN and 5ml of 7ml is heated to 70 DEG C, and continue 24 hours, solution is concentrated, and adds the water of Cl3CH and 40ml of 85ml.Organic layer is with after normal saline washing, and drying is also concentrated.Residue then with chromatography purification (SP1 system, Cl2CH2 to Cl2CH2/EtOH 9:1), and obtains the pure title compound (43% productive rate) of 170mg.
Intermedium 157
Trans-4-[[4-(the chloro-4-formoxyl of 2--5-methoxy phenoxy) butyl] (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
The intermedium 156 of 170mg (0.29mmol) is dissolved in the chloroform of 3.9ml.Added in 45 minutes by the MnO2 of the activation of 321mg (3.14mmol), system then stirs 3 hours in 45 DEG C in batches.Inorganic matter, by after leaching, rinse, and filtrate being concentrated obtains the title compound of 167mg with the Cl3CH of 48ml, and its purity is enough for lower step.
Intermedium 158
Trans-4-[4-[4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen }-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-base) ethyl] amino phenyl) the chloro-5-methoxy phenoxy of-2-] butyl-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
The diisopropylethylamine of the 5-of the intermedium 157 of 163mg (0.26mmol), 125mg (0.32mmol) ((1R)-2-amino-1-{ [tert-butyl (dimethyl) silicyl] oxygen } ethyl)-oxine-2 (1H)-one acetate (prepared by the preparation 8 according to US20060035931) and 0.056ml (0.32mmol) is dissolved in the methanol of 1.3ml, then adds the triacetyl oxygen sodium borohydride of 117mg (0.52mmol).System, in stirred at ambient temperature 3.5 hours, after solvent removes under vacuum, then adds the 4%NaHCO3 of 16ml.Quench with the acetyl triethyl of 120ml afterwards and get compound, solution is dry, concentrated, gained residue again to prepare reversed-phase HPLC (system 2) purification, and obtains the title compound (71% productive rate) of 173mg.
Example 25
Trans-4-[{ 4-[the chloro-4-of 2-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxy phenoxy] butyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate hydrofluoride (1:2)
The intermedium 158 of 170mg (0.18mmol) is dissolved in the THF of 9ml.Add the Et3N (HF) 3 of 0.13ml (0.80mmol) again.Solid residue, stirred at ambient temperature whole evening, is poured out, with MeCN process, filtration, and is obtained the title compound (88% productive rate) of 136mg by system.
LRMS(m/z):796(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.44(br.s.,4H)1.66(br.s.,2H)1.80(br.s.,4H)1.98(br.s.,2H)2.30(s,3H)2.58-2.67(m,2H)2.80(br.s.,2H)3.84(s.,3H)4.15(br.s.,2H)4.75(br.s.,1H)5.21(br.s.,1H)6.53(d,J＝9.05Hz,1H)6.78(s.1H)6.93–7.04(m,2H)7.11(m.,3H)7.31(br.s.,1H)7.41(s.,1H)7.51(d,J＝7.5Hz,2H)8.18(d,J＝9.05Hz,1H)
Intermedium 159
Trans-4-[2-[([4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen }-2-(5-hydroxyl-3-oxygen-3,4-dihydro-2H-1,4-benzene oxazines-8-base) ethyl] amino methyl) the chloro-5-anisyl of-2-]-amino carbonyl) oxygen base] ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
By 8-[(R)-2-amino-1-(tert-butyl-dimethyl-silane oxygen base)-ethyl-5-hydroxyl-4H-phenyl [1 of 100mg (0.25mmol), 4] oxazines-3-ketone (prepared by the described of intermedium 65 according to WO2008149110), the intermedium 62 of 196mg (0.26mmol) and the diisopropylethylamine of 0.045ml (0.26mmol) are dissolved in the MeOH of 3ml, then add the triacetyl oxygen sodium borohydride of 157mg (0.75mmol).System, in stirred at ambient temperature 2.5 hours, adds the triacetyl oxygen sodium borohydride of 50mg (0.24mmol) afterwards, and stirs whole evening, add the hydride of three parts of 50mg again, often add a stirring 2 hours, remove solvent afterwards, residue is then with the 4%NaHCO3 solution-treated of 20ml.System is thoroughly quenched with ethyl acetate and is got, in addition dry, concentrated again, and obtain the compound coarse fodder of 220mg, then through chromatography purification (SP1, wash with Cl3CH to Cl3CH/MeOH 9:1), and obtain the title compound (59% productive rate) of 147mg.
Example 26
Trans-4-[{ 2-[({ [the chloro-4-of 2-({ [(2R)-2-hydroxyl-2-(5-hydroxyl-3-oxygen-3,4-dihydro-2H-1,4-phenyl oxazines-8-base) ethyl] amino methyl)-5-anisyl] amino carbonyl)-oxygen base] ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate
The intermedium 159 of 140mg (0.15mmol) is dissolved in the THF of 6ml.The Et of 0.15ml (0.94mmol) is added again under argon gas atmosphere 3n (HF) 3.System in stirred at ambient temperature 18 hours, and with acetone/the dry ice bath by external refrigeration.Remove floating thing above, and oily residue adds with 8ml THF and the floating thing abandoned after stirring 5 minutes above.Residue, with 8ml MeCN process 10 minutes, by solid leaching, after a small amount of MeCN and washed with ether, in 40 DEG C of dryings 2 hours in vaccum dewatering device, and obtains the pure title compound (52% productive rate) of 68mg.
LRMS(m/z):815(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.36(m.,4H)；1.72(m.,2H)；1.91(m.,2H)；2,22(s.,3H)；2.42(b.s.,1H)；2.58(m.,2H)；2.65(m.,2H)；3.75(m.,5H)；4.10(m.,2H)；4.46(s.,2H)4.70(b.s.,1H)；4.89(b.s.,1H)；6.49(d.,J＝6Hz,1H)；6.86(d.,J＝6Hz,1H)6.95-6.99(m.,2H)；7.06(m.,2H)；7.20(s.,1H)；7.25(b.s.,1H)；7.37(s.,1H)；7.47(d.,J＝6Hz；1H)；8.99(s.,1H)；9.92(b.s.,1H).
Intermedium 160
Methyl 9-methyl-9H-xanthene-9-hydroxy acid salt
Be dissolved in after in the THF of 70ml by the methyl-9H-xanthene-9-hydroxy acid salt of 3.25g (13.53mmol), with ice bath cooling, then instill the 2M LDA solution of 10.15ml (20.29mmol), holding temperature is in 0 DEG C simultaneously.Then at room temperature stir after 1 hour, the iodomethane of instillation 1.68ml (27.06mmol), system is stirred at ambient temperature whole evening.Solution is poured in the saturated solution of ammonium chloride, gets three times by ether essence.After normal saline washing, solution is dry, concentrated, obtain pale red residue, then use column chromatography purification (Cl 3cH/ hexane is by 1:3 to 1:1), and obtain the title compound (75% productive rate) of the white solid of 2.6g.
Intermedium 161
Trans-4-[(uncle-butoxy carbonyl) (methyl) is amino] cyclohexyl 9-methyl-9H-xanthene-9-carbonyl hydrochlorate
The intermedium 3 of the intermedium 160 of 405mg (1.59mmol) and 420mg (1.83mmol) is dissolved in the benzene of 40ml.Add the sodium hydride (60% paraffin wax suspends) of 32mg (0.80mmol) again.In 150 DEG C of Distallation systms (outer bath) until have collected the toluene of 30ml, then add the toluene of 30ml, and redistillation.Same operation repeats secondary.Solvent is removed under vacuum, and residue is separated in ether/4% aqueous solution NaHCO3.Organic layer with dry after salt water washing and concentrated, and obtains the flaxen grease of 650mg, and it can be used for lower step containing the title compound of 83%.
Intermedium 162
Trans-4-(methylamino) cyclohexyl 9-methyl-9H-xanthene-9-carbonyl hydrochlorate
The intermedium 161 (83% purity) of 650mg (1.19mmol) is dissolved in the dioxanes of 2.5ml, then adds the solution of 4M HCl in dioxanes of 0.5ml (2.0mmol).System in stirred at ambient temperature 2 hours, then adds the solution of 4M HCl in dioxanes of 0.5ml, and stirs whole evening.Add ether and water afterwards, and with potassium carbonate alkalization aqueous layer to pH 9, then get secondary with ethyl acetate essence.Drying and concentrated after, obtain the title compound (63% productive rate) of the pale brown oil of 318mg.
Intermedium 163
Trans-4-[(9-bromine nonyl) (methyl) is amino] cyclohexyl 9-methyl-9H-xanthene-9-carboxylate
The intermedium 162 of 318mg (0.90mmol) is dissolved in the THF of 12ml, then adds 1,9-bis-bromononane of 0.728ml (3.61mmol), and the triethylamine of 0.19ml (1.36mmol).System stirs after 24 hours at 50 DEG C, adds the triethylamine of 0.19ml, and stirs whole evening at 50 DEG C, then adds 1,9-bis-bromononane (0.911ml; 4.5mmol) and after stirring 72 hours in 70 DEG C, remove solvent, add ether, leaching solid (three second ammonium bromine hydrides), concentrates filtrate, through SP1 chromatography purification, obtains the title compound (42% productive rate) of 220mg.
Intermedium 164
Trans-4-[(9-{ [(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-base) ethyl] amino nonyl) (methyl) amino] cyclohexyl 9-methyl-9H-xanthene-9-carboxylate
(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen by the intermedium 163 of 220mg (0.40mmol), 156mg (0.40mmol) }-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-base) solution of sodium bicarbonate in 5ml dimethyl acetylamide of second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) and 140mg (1.66mmol) stirs whole evening at 60 DEG C, solvent removes under vacuo, and residue is then separated with ethyl acetate/water.Drying after organic layer rinses with water is also concentrated, and gained residue obtains the title compound (29% productive rate) of 93mg with chromatography purification (SP1 system is washed with Cl3CH to Cl3CH/EtOH 9:1).
Example 27
Trans-4-[(9-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-base) ethyl]-amino } nonyl) (methyl) amino] cyclohexyl 9-methyl-9H-xanthene-9-carboxylate
The intermedium 164 of 68mg (0.08mmol) is dissolved in the THF of 2ml.With the triethylamine three hydrofluoride complexation of 0.068ml (0.42mmol).System stirs 4 hours under an argon atmosphere in room temperature.Remove supernatant, residual faint yellow oil stirs afterflush in whole evening with more THF again, then removes solvent, residue then in vaccum dewatering device at 30 DEG C dry whole evening.Then obtain the solid title compound (100% purity UPLC, 46% productive rate) of 30.0mg.
LRMS(m/z):696(M+1) +.
1H NMR(300MHz,DMSO-d 6)ppm 1.17-1.37(br.s.,18H)1.44-1.65(br.s.,4H)1.67-1.79(c.s.,6H)2.11(s.,3H)2.25-2.38(br.s.,4H)2.75(t.,2H)2.87(br.s.,2H)3.60(m.,1H)4.57(m.,1H)；5.18(m.,1H),6.53(d.,J＝12Hz,1H),6.93(d.,J＝6Hz,1H)7.06-7.16(c.s.,5H)7.23-7.34(c.s.,4H)8.16(d.,J＝6Hz,1H).
Intermedium 165
Trans-4-[(uncle-butoxy carbonyl) (methyl) is amino] cyclohexyl (2R)-cyclopenta (hydroxyl) phenyl acetate
The carbonyl dimidazoles of 1320mg (8.14mmol) is added (2R)-cyclopenta (hydroxyl) the phenyl acetic acid of 1500mg (6.81mmol) (according to J.Med.Chem.1977,20 (12), prepare described in 1612-17 and WO2002/053564) solution in the THF of 20ml, in stirring at room temperature after 2 hours, add the carbonyl dimidazoles of 1000mg, and stir 2 hours again.Afterwards, the sodium hydride of 300mg (7.50mmol) 60% is added the solution of intermedium 3 in 20ml THF of 2810mg (12.25mmol), system was in stirred at ambient temperature 3 hours.The solution of imidazolide is added the solution of hydrocarbon oxide, gained system, stirred at ambient temperature whole evening, afterwards, is poured in other ice/water, and quenches with ether and get.Organic layer is successively with 4%Na-HCO3 solution, water and normal saline washing, and after dry, concentrated under vacuo, residue to prepare reversed-phase HPLC (hexane is to Cl3CH) purification, and obtains the pure title compound (65% productive rate) of 1900mg.
LRMS(m/z):432(M+1)+.
Intermedium 166
Trans-4-(methylamino) cyclohexyl (2R)-cyclopenta (hydroxyl) phenyl acetate
The intermedium 165 of 2.08g (4.82mmol) is dissolved in the dioxanes of 60ml, then adds the solution of 4N hydrogen chloride in dioxanes of 9.50ml.System was in stirred at ambient temperature 72 hours, and after the separation of diethyl ether/water, aqueous solution washed with ether, with solid carbonic acid potash, then gets by ethyl acetate essence, drying and concentrated after, obtain the pure title compound of the colorless oil of 1.37g.
LRMS(m/z):332(M+1)+
Intermedium 167
Trans-4-[(2-hydroxyethyl) (methyl) is amino] cyclohexyl (2R)-cyclopenta (hydroxyl) phenyl acetate
By intermedium 166, according to the same steps described in intermedium 60, the title compound (58% productive rate) of colorless oil can be obtained.
LRMS(m/z)：376(M+1)+
Intermedium 168
Trans-4-[{ 2-[({ [2-chloro-4-(hydroxymethyl)-5-anisyl] is amino } carbonyl) oxygen base] ethyl } (methyl) is amino] cyclohexyl (2R)-cyclopenta (hydroxyl) phenyl acetate
By intermedium 167 and 59, according to the same steps described in intermedium 61 and 62, then with preparing reversed-phase HPLC (hexane/diethyl ether 10:0 to 5:5) purification, and obtain the title compound (30% productive rate) of colorless oil.
LRMS(m/z):589(M+1)+
Intermedium 169
Trans-4-[[2-({ [(2-chloro-4-formoxyl-5-anisyl) is amino] carbonyl } oxygen base) ethyl] (methyl) is amino] cyclohexyl (2R)-cyclopenta (hydroxyl) phenyl acetate
By intermedium 168, according to the same steps described in intermedium 43, title compound (77% productive rate) can be obtained.
LRMS(m/z):587(M+1)+
Intermedium 170
Trans-4-[2-[([4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2-chloro-5-anisyl] amino carbonyl) oxygen base] ethyl (methyl) amino] cyclohexyl (2R)-cyclohexyl (hydroxyl) phenyl acetate
By intermedium 169 and (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen }-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) beginning, according to the same steps described in intermedium 64, again with preparing reversed-phase HPLC (CH2Cl2/EtOH 10:0 to 9:1) purification, and obtain title compound (54% productive rate).
LRMS(m/z):905(M+1)+
Example 28
Trans-4-[{ 2-[({ [the chloro-4-of 2-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl) oxygen base] ethyl }-(methyl) is amino] cyclohexyl (2R)-cyclopenta (hydroxyl) phenyl acetate
By intermedium 170, according to the same steps described in example 12, title compound (37% productive rate) can be obtained.
LRMS(m/z):791(M+1)+.
1H-NMR(300MHz,DMSO-d6).ppm:1.12-1.61(m,12H),1.63-1.82(m,3H),1.86-1.95(m,1H),2.21(s,3H),2.37-2.45(m,1H),2.60-2.68(m,2H),2.69-2.89(m,3H),3.74(s,5H),4.05-4.14(t,2H),4.50-4.62(m,1H),5.06-5.14(m,1H),5.54(s,1H),6.50(d,J＝9.89Hz,1H),6.92(d,J＝7.97Hz,1H),7.07(d,J＝7.97Hz,1H),7.16-7.40(m,5H),7.53-7.60(m,2H),8.11(d,J＝9.89Hz,1H),8.97(s,1H),10.35(br.s.,1H).
Intermedium 171
Trans-4-[(uncle-butoxy carbonyl) (methyl) is amino] cyclohexyl (2S)-cyclopenta (hydroxyl)-2-thienyl acetate
The carbonyl dimidazoles of 387mg (2.39mmol) is added it (2S)-cyclopenta (hydroxyl) 2-thienyl acetic acid of 450mg (1.99mmol) (according to J.Med.Chem.1977,20 (12), prepared by described in 1612-17 and WO2002/053564) solution in 6ml THF, in stirred at ambient temperature after 3 hours, add the carbonyl dimidazoles of 387mg, and stir 2 hours, again 60% sodium hydride of 87mg (2.18mmol) is added the solution of intermedium 3 in 2ml THF of 822mg (3.58mmol), and in stirred at ambient temperature 5 hours.Afterwards, imidazolide solution is added the solution of hydrocarbon oxide, and stirred at ambient temperature whole evening, solution is poured in other ice/water, and gets with ether (2x100ml) essence.Organic solution is successively rinsed with 4%NaHCO3 solution, water and saline, under vacuo dry and concentrated after, can containing the pale yellow oil of the 1048mg of 60% title compound, it can be used for lower step.
Intermedium 172
Trans-4-(methylamino) cyclohexyl (2S)-cyclopenta (hydroxyl) 2-thienyl acetate
The intermedium 171 of 1048mg (1.44mmol) is dissolved in the dioxanes of 24ml, then adds the solution of 4N hydrogen chloride in dioxanes of 4.80ml.System in stirred at ambient temperature 24 hours, through diethyl ether/moisture every after, water-soluble liquid phase is with washed with ether, with solid carbonic acid hydrogen potash, get with ethyl acetate essence again, drying and concentrated after, the pure title compound of colorless oil (59% productive rate) of 295mg can be obtained.
LRMS(m/z):338(M+1)+
Intermedium 173
Trans-4-[(2-hydroxyethyl) (methyl) is amino] cyclohexyl (2S)-cyclopenta (hydroxyl) 2-thienyl acetate
By intermedium 172, according to the same steps described in intermedium 60, the title compound (73% productive rate) of colorless oil can be obtained.
LRMS(m/z):382(M+1)+
Intermedium 174
Trans-4-[{ 2-[({ [the chloro-4-of 2-(hydroxymethyl)-5-anisyl] is amino } carbonyl) oxygen base] ethyl } (methyl) is amino] cyclohexyl (2S)-cyclopenta (hydroxyl) 2-thienyl acetate
By intermedium 173 and 59, according to the same steps described in intermedium 61 and 62, then to prepare reversed-phase HPLC (Cl2CH2/MeOH 10:0 to 9:1) purification, the title compound (50% productive rate) of colorless oil can be obtained.
LRMS(m/z):595(M+1)+
Intermedium 175
Trans-4-[[2-({ [(the chloro-4-formoxyl of 2--5-anisyl) is amino] carbonyl } oxygen base) ethyl] (methyl) is amino] cyclohexyl (2S)-cyclopenta (hydroxyl) 2-thienyl acetate
By intermedium 174, according to the same steps described in intermedium 43, title compound (86% productive rate) can be obtained.
LRMS(m/z):593(M+1)+
Intermedium 176
Trans-4-[2-[([4-([(2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen base }-2-(8-hydroxyl-2-oxygen-
1,2-dihydroquinoline-5-base) ethyl] amino methyl)-2-chloro-5-anisyl] amino carbonyl) oxygen] ethyl (methyl) amino] cyclohexyl (2S)-cyclopenta (hydroxyl) 2-thienyl acetate
By intermedium 175 and (2R)-2-{ [tert-butyl (dimethyl) silicyl] oxygen }-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-base) second ammonium acetate salt (prepared by the preparation 8 according to US20060035931) beginning, according to the same steps described in intermedium 64, again with preparing reversed-phase HPLC (CHCl3/EtOH 10:0 to 9:1) purification, title compound (72% productive rate) can be obtained.
LRMS(m/z):911(M+1)+
Example 29
Trans-4-[{ 2-[({ [the chloro-4-of 2-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxygen-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl)-oxygen base] ethyl } (methyl) is amino] cyclohexyl (2S)-cyclopenta (hydroxyl) 2-thienyl acetate
By intermedium 176, according to the same steps described in example 12, title compound (59% productive rate) can be obtained.
LRMS(m/z):797(M+1)+.
1H-NMR(300MHz,DMSO-d6)□ppm:1.18-1.58(m,12H),1.65-1.77(m,2H),1.78-1.86(m,1H),1.89-2.00(m,1H),2.22(s,3H),2.37-2.47(m,1H),2.61-2.69(m,3H),2.70-2.77(m,J＝5.22Hz,2H),3.74(s,3H),3.77(s,2H),4.10(t,J＝5.77Hz,2H),4.53-4.65(m,1H),5.11(t,J＝5.91Hz,1H),5.94(s,1H),6.49(d,J＝9.89Hz,1H),6.89-6.98(m,2H),7.05(s,1H),7.06-7.09(m,1H),7.20(s,1H),7.37(s,1H),7.38(d,J＝1.10Hz,1H),8.12(d,J＝9.89Hz,1H),8.99(s,1H)10.37(br.s.,1H).
Biological test
Test 1: human adrenal's element can β 1and β 2the binding analysis of receptor
Be attached to the research and utilization coml thin film of human adrenal's element energy β 1 and beta 2 receptor, this thin film is prepared (Perkin Elmer) by the Sf9 cell of overexpression.Membrane suspension thing (β 1 be 16 μ g/well, β 2 be 5 μ g/well) is at analysis buffer agent (75mM Tris/HCl, containing 12.5mM MgCl2 and 2mM EDTA, pH=7.4) cultivate in, cultivate with the 3H-CGP12177 (Amersham) of 0.14nM or 0.6nM respectively β 1 and beta 2 receptor, its final volume is 250 μ l.It is being used in the GFC Multiscreen 96 well plate containing the analysis buffer agent process of 0.3%PEI (Sigma) (Millipore) before.When there being the propranolol of 1 μM, non-special combination can be measured.Cultivate under room temperature, and maintain 60 minutes under mitigation shake.To filter and to use the Tris/HCl 50mM pH=7.4 of 2.5 volumes to rinse, stop association reaction.Decide the affinity of each test compounds to receptor by ten different concentration, and do secondary.Utilize and calculate IC50s from the Activity Base software of IDBS and four parameter-log equations.
The preferred compound of the present invention for beta 2 receptor, its IC 50value is less than 20nM, is preferably less than 10nM.
Test 2: mankind's muscarine M 1, M 2, M 3, M 4and M 5the binding analysis of receptor
The coml thin film (Perkin Elmer) prepared by CHO-K1 cell is utilized to implement to be attached to the research of the mankind's muscarine M1, M2, M3, M4 and M5 receptor.Be implement radioligand-binding study in the 96 polypropylene well plates of 200 μ l at total measurement (volume).Except being dissolved in the compound of DMSO 100%, all the other all reagent are all dissolved in analyzes binding buffer agent (PBS, the SIGMA of calcic and magnesium).In the situation of atropine having 1 μM, non-special combination (NSB) can be measured.Using [3H]-NMS as radioligand, for M2, M3 and M5, its concentration is 1nM, and for M1 and M4, its concentration is 0.3nM.[3H]-NMS and antagonist thin film breed, and described thin film expresses the mankind's M-ChR M1, M2, M3, M4 and M5 with the concentration of 8.1 μ g/well, 10 μ g/well, 4.9 μ g/well, 4.5 μ g/well and 4.9 μ g/well respectively.
Cultivate 2 hours under mitigation shake after, the reactant mixture of 150 μ l was transferred in 1 hour the 96GF/C filter plate (Millipore) containing 0.05%PEI (Sigma), wash buffer (Tris 50mM used in advance by this filter plate; NaCl 100mM; PH:7.4) processed.In conjunction with the rapid vacuum filtration in from the menifold of Millipore of [3H]-NMS be freely separated, and rinse four times with ice-cold wash buffer agent.After drying in 30 minutes, the OPTIPHASE Supermix of 30 μ l is added in each well, and utilize Microbeta microplate to glisten enumerator to quantize radioactivity.
By using ten kinds of different concentration to determine the affinity of each test compounds to receptor, and do secondary.Use the Activity Base software from IDBS and four parameter-log equations calculating IC50s.
Preferred compound show needle of the present invention is to M 3the IC of receptor 50be worth between 0.1nM and 10nM, preferably between 0.1nM and 5nM, more preferably between 0.1nM and 2nM.
Test 3: the β of the guinea pig trachea ring of isolation 2the activity of adrenoceptor agonists and effect duration
By compound dissolution is prepared former medicine in distilled water.Its some be dissolved in maximum 10% polyethylene glycol 300 and/or 1% HCl 1N in.The supply of isopropyl (nor-) epinephrine Hemisulphate, from Sigma (code I 5752), is dissolved in distilled water.Then Krebs Henseleit solution (NaCl 118mM, KCl 4.7mM, CaCl22.52mM is used, MgSO41.66mM, NaHCO324.9mM, KH2PO41.18mM, glucose 5.55mM, Sodium Pyruvate 2mM) dilute stock solution, to prepare the various compounds of variable concentrations.
The activity of the compound in annulus trachealis is according to (Eur J Pharmacol.1991,198,171-176) assessments such as Cortijo.In brief, it is made to sacrifice by the head of thumping male guinea pig (400-500g) adult, and then blood-letting (ventral aorta).Excise trachea again, put into the Krebs solution of Petri dish.Dissect the tissue that attachment connects, by Krebs solution irrigation lumen lenitively.Each trachea is cut into independent ring.First, the cartilage of smooth muscle two side connects with cotton thread.Cut the cartilage of smooth muscle opposite side to open ring, then, one end of ring is connected to strain gauge, and the other end is connected to organ bath with the resting tension of 1g, utilize the change of the tension force of isometric transducer TRI 201,202 (Panlab, Spain) measurement ring.Tissue resident 1 hour, make it stablize and be suspended in water-jacket typ organ bath, this water-jacket typ organ bath contains the Krebs solution of the 30ml of 37 DEG C, and squeezes into bubbling with the oxygen of 5%CO2.
When experiment starts, adding concentration is that isopropyl (nor-) epinephrine of 0.1 μM is to test the lax of annulus trachealis.Then rinse twice with Krebs solution, juxtaposition stays 15-30 minute to make it restore.To each compound, implement one increase and accumulation concentration (0.01nM is to 0.1 μM), each time execution between have a maximum waiting time: 30 minutes.Again after ceiling effect (reaching completely lax), in 1 hour, every 15 minutes gas washing pipe rings once.At the end of experiment, add isopropyl (nor-) epinephrine of 0.1 μM to each sample, to obtain maximum relax level.
Agonist activity is determined by the concentration measuring the test cumulative rises of the test compounds of the preparation in system analysis Krebs solution of synergist activity.The magnitude of size of each reaction is measured in measurement, and to represent with the maximum lax percentage ratio caused relative to isopropyl (nor-) epinephrine.The effect value of test compounds (causes 50% lax required concentration, EC with absolute terms 50) represent.
To often kind of compound, from medicine add terminate to 50% recover institute across time (T50 skew, the tool maximum time of 60 minutes) also measured.
Preferred compound display EC of the present invention 50value is less than 3nM.
Test 4: the β in electricity irritation mouse left atrium 1the activity of adrenoceptor agonists
By compound dissolution being obtained in distilled water prepare former drug solution.One be partially dissolved in 10% of maximum polyethylene glycol 300 and/or 1% 1N HCl.Isopropyl (nor-) epinephrine Hemisulphate is supplied by Sigma (code I 5752), is dissolved in distilled water.Then, original solution is diluted in Krebs Henseleit solution (NaCl 118mM, KCl 4.7mM, CaCl22.52mM, MgSO41.66mM, NaHCO324.9mM, KH2PO41.18mM, glucose 5.55mM, Sodium Pyruvate 2mM), and obtain each compound of variable concentrations.
Being done to swoon by male Wistar rat (150-250g) and breaking cervical region makes it dead.Its heart is removed and puts into foregoing Krebs solution.Cut off by left atrium and be suspended in water-jacket typ organ bath, water-jacket typ organ bath contains the Krebs solution of 30ml, and temperature is 37 DEG C, and squeezes into bubbling with the oxygen of 5%CO2.The left atrium be separated is connected to isometric strength sensor TRI 201,202 (Panlab, Spain) with cotton thread under the resting tension of 0.5g.Sensor is connected to PowerLab system 8/30 (ADInstruments, Australia) to measure the change of tension force.Tissue is with electrical field stimulation device Hugo Sachs Electronic type D7806 (Harvard Apparatus, Germany) stimulate, frequency is 1Hz (superpower voltage, 0.1ms), and indwelling 45 minutes, make it stable to measure basic contraction.
Isopropyl (nor-) epinephrine 1 μM is added secondary in balneation, the reaction of test atrium.After the reaction of test atrium, rinse organ secondary with Krebs solution, and indwelling about 15 minutes is to make it recover.To increase and the concentration (1nM is to 10 μMs) of accumulation, every 10-15 minute adds compound, to read stable effect.After last compound concentration assessment, wash atrium with Krebs solution, then add isopropyl (nor-) epinephrine of 1 μM, whether reach maximum contraction to investigate.
By by the contraction phase caused by the compound of each dosage for isopropyl (nor-) epinephrine of 1 μM the reaction that rises quantized and determined that β 1 is active, isopropyl (nor-) epinephrine of 1 μM is considered to maximum, therefore equals 100%.Set up corresponding accumulation response curve (CRCs), cause the concentration needed for maximum collapse effect of 50% to be then expressed as effect value (EC 50).
The preferred compound display of the present invention, the EC of test 4 50value and the EC testing 3 50ratio between value is more than 1000 times.
Test 5: the skew of the activity of the muscarine antagonist in electricity irritation guinea pig trachea and beta-adrenergic agonist, the beginning of effect and effect
Thumped by the head of the male guinea pig (400-500g) of growing up, then blood-letting makes it dead.Trachea is cut off and is placed in the Krebs solution of Petri dish.The tissue of bonding is dissociated, and inner chamber then rinses lenitively with Krebs solution, and each trachea is dissociated into the ring containing 3-4 zona cartilaginea, is cut off by the cartilage of smooth muscle opposite edge, makes ring open and form band.The cartilage of one end of band is connected to strain gauge with a long cotton thread, and the cotton ring of the other end is used for tissue to be fixed in perfusate chamber.
The method of tissue perfusion is described (Coleman & Nials, 1989).Prepared product is shelved in Superfusion bath Type 840 (Harvard Apparatus, Germany) under the resting tension of 1g.In whole experimentation, band 37 DEG C, containing in the Krebs Henseleit solution of 2.8 μMs of indomethacins, inflation (O2 of 5%CO2) situation under, with the speed perfusion of 2ml/min.Two parallel storings of platinum electrode and extremely near tissue.Afterwards, organize by storing 1 hour with stable.
The method can appear the activity of all relaxants, comprises muscarine Antagonism and β 2 is building performance.In order to the activity of the muscarine antagonist of compound will be disclosed, beta antagonists (ultimate density is the propranolol of 1 μM) is added in Krebs solution, for all analyses, containing the Krebs solution of propranolol by perfunded.
Every 2 minutes, the square-wave pulse of 10-serial second provided electricity irritation, and frequency is 5Hz, and action time is 0.1ms (Coleman & Nials, 1989).In each experiment, in the maximum reaction of 10-15%, select over much dosage according to the response curve relevant with voltage of 8-16V, select voltage.In order to set up baseline, trachea band reaches minimum 20 minutes (10 peak values) by electricity irritation under this super large voltage.
Compound dissolution is prepared former drug solution in distilled water, and some of them are dissolved in 10% polyethylene glycol 300 of maximum and/or the 1N HCl of 1%.Afterwards, original solution is diluted in Krebs Henseleit, and obtains each compound of variable concentrations.
Activity is determined by the test compounds of the concentration injecting increase in 60 minutes.Measure the amplitude of each reaction, and represent with the percentage ratio of the suppression of electroinitiation contractile response baseline.Effect value for muscarine antagonist and beta-adrenergic agonist then (causes the concentration needed for 50% suppression, EC with absolute term 50) represent.After the test compounds concentration 60 minutes of 50%-80% injecting the maximum collapse amount that can relax, determine the persistent period acted on.
T 50start to be defined as reaching maximum reaction (T from medicine adds max) 50% time crossed over.T maxbe defined as reaching the time that maximum reaction crosses over from medicine adds.T 50skew is defined as adding from medicine terminating to reach for 50% lax time of recovering to cross over.The skew of effect also can be expressed as medicine add terminate after 8 hours reach the percentage ratio of recovery.
The compound display that the present invention selects is to all active EC 50value is less than 5nM, assesses then EC to M3 50value is less than 10nM, T 50deviant is greater than 450 minutes.
Test 6: the airway constriction that acetylcholine or histamine cause the Cavia porcellus of paralysis
This in vivo analyzes the trachea protective effect for assessing test compounds, and these compounds demonstrate the activity of muscarinic receptor antagonist and beta 2 adrenoreceptor agonists.
Test compounds is dissolved in distilled water, and some of them need to use 1%HCl or 1%NaOH of maximum and/or 2% polyethylene glycol 300 to dissolve.Acetylcholine chloride, histamine dihydrochloride and propranolol hydrochloride provided by Sigma-Aldrich (St.Louis, Mo, USA), are dissolved in saline solns.
Under with 10 indoor air circulations per hour male guinea pig (450-600g) being maintained the humidity of the temperature of 22 ± 2 DEG C and 40%-70%.They are before using test compounds, stand 12 hours artificial light circulation (from the morning 7 time to afternoon 7 time), and minimum 5 days adaptive time sections.Before experiment, these animal fasting 18 hours, only arbitrarily feed water.
Cavia porcellus is exposed in the aerosol of test compounds or test media.These aerosols utilize Devilbiss nebulizer (Model Ultraneb 2000, Somerset, PA, USA) to be produced by aqueous solution.Admixture of gas (CO 2=5%, O 2=21%, N 2=74%) with 3L/min data rate stream through nebulizer.Nebulizer is connected to the box (17x17x25cm) of methacrylate, and in it, per a period of time puts into an animal.Each Cavia porcellus total time rested in box is 10 minutes, and each compound or medium, when time 0 and 5 minutes, are atomized 60 seconds (solution atomization of about 5mL).
The concentration of aerosolized compound is between 0.1 μ g/ml and 100 μ g/ml.The assessment FinePointe of the trachea protective effect of test compounds tMrC system (Buxco Research Systems; Wilmington, NC, USA) after the tablet has been ingested 1 hour or 24 hours time carry out.
By carrying out anaesthetized guinea pig with the capable intramuscular injection of ketamine of the dose of 1ml/kg (69.8mg/Kg), xylazine (5.6mg/Kg) and acepromazine (1.6mg/Kg).If necessary, can in addition before intramuscular injection institute's anesthesia cocktail of carrying to increase anesthesia.Afterwards, by animal intubate, put into volume recorder (#PLY4214, Buxco Research Systems; Wilmington, NC, USA), wherein temperature maintains 37 DEG C.Ventilation pump is configured to the moisture volume of 10ml/kg and the speed of tool 60 breaths/min.Insert the driving pressure that pulmonary measured by food meatus.Jugular vessel is also inserted with polyethylene tube (Portex Ld.), is used for the interval intravenous injection of 3 minutes to carry acetylcholine or histamine.Once chamber is closed, just utilize the respiration rate recorder be positioned on the wall of plethysmograph to measure stream.Utilize FinePointe tMrC system (Buxco Research Systems; NC, USA) record these flowings and the change of pressure, and assess airway resistance (RI) (BioSystem XA software, the version 2.10 for Windows of anesthetized animal; Buxco Research Systems; NC, USA).
Once baseline value is in the airway resistance scope of per second 0,1-0,3cmH2O/mL, just start the measurement of pulmonary.After section stabilization time (3-5 divides), cause airway constriction by secondary vein injection acetylcholine (10 μ g/kg and 15 μ g/kg) or histamine (5 μ g/kg and 10 μ g/kg).The airway constriction reaction of the acetylcholine of 15 μ g/kg is used for calculating the total depression effect of each processed group compared to the reaction of its corresponding matched group.When vein injects histamine (10 μ g/kg) to cause airway constriction, the suppression of this reaction in processed group reflects the activity of beta 2-adrenergic receptor agonists.In addition, in order to isolate the activity of muscarine antagonist in the airway constriction model caused by acetylcholine, when injecting first 15 minutes of acetylcholine, inject propranolol (5mg/kg, intravenous injection) to animal, this compound can block the activity of beta receptor.
In following three different situations, the concentration of the test compounds of the suppression of the airway constriction of 50% (IC50) is caused to establish often kind of gas main blockage effect of compound and the analysis of β2agonists and antimuscarinic activity thereof sucked by assessment: the activity of the beta 2-adrenergic receptor agonists after the contraction of gas that histamine causes, the activity of muscarinic receptor antagonist when injecting propranolol before the airway constriction that acetylcholine causes, and two kinds of active combinations when the airway constriction of acetylcholine initiation is suppressed.
The effect of all compounds littlely to be tested after the tablet has been ingested for 1 hour and 24 constantly, to assess the acting duration of the activity of gas main protection, and the composition of independent beta 2-adrenergic receptor agonists and muscarinic receptor antagonist.
The compound display IC that the present invention selects 50value is littlely less than 5 μ g/ml constantly 1, is littlely less than 25 μ g/ml constantly 24.
Pharmaceutical composition
Pharmaceutical formulation can represent with unit dose easily, and it can utilize any method known on pharmaceutical field to prepare.All methods include step active ingredient being inserted carrier medium.Usually, by active ingredient evenly and closely insert liquid-carrier or fine solid carrier or the two to prepare formula, product can be molded into desired shape if necessary.
The present invention is suitable for oral formula can make discrete unit, such as capsule, cachet or tablet, and it respectively contains the active ingredient of a predetermined close; Do powdered or microgranule; Make solution or the suspended substance in water liquid or the suspended substance in non-water liquid; Or make O/w emulsion or Water-In-Oil supernatant liquid.Active ingredient also can be made into pill, sugared agent or unguentum.
Syrup formula generally includes compound or salt at the suspension of liquid carrier or solution, and liquid-carrier comprises such as ethanol, Oleum Arachidis hypogaeae semen, olive oil, glycerol or water, and it contains flavoring agent or toner.
When compositions is tablet, the pharmaceutical carrier that solid for mulation is conventional can be used.The example of these carriers comprises magnesium stearate, Pulvis Talci, animal glue, natural gum, stearic acid, starch, lactose and sucrose.
Tablet can utilize compacting or be molded to be formed, and it is optionally containing one or more auxiliary ingredients.Slugging forms by being suppressed by free-pouring active ingredient (as powder or microgranule, optionally with bonding agent, lubricant, inert diluent, surfactant or dispersant) in suitable machine.
Molded tablets forms by being molded by the mixture of powder compounds and inert liquid diluent in suitable machine.Tablet optionally can cover skin or mark, and it also can be formulated into and slowly or controllably can discharge active ingredient.
When compositions is hard capsule, any conventional encapsulation is all applicable, such as, uses the carrier in aforesaid hard capsule.When compositions is soft capsule, any pharmaceutical carrier preparing dispersant or suspending agent conventional all can be considered, such as watery glue, cellulose, silicate or oil preparation, and is merged in soft capsule.
Can insert in the involucrum of capsule or animal glue for sucking the dry powder composition delivering to pulmonary, or in the clamshell of laminated aluminium foil, in inhaler or insufflator.Formula generally contains suction powder and suitable powder binder (carrier mass) the such as lactose or starch of compound of the present invention, better with lactose.
Each capsule or Nang Bao are generally containing each therapeutically active composition between 2 μ g and 150 μ g, or active ingredient does not need adjuvant and is produced.
The packaging of formula can be suitable for unit dose or multi-agent.In the situation of multi-agent, measure again when formula can measure in advance or use.Therefore, dry powder inhaler can be divided into three kinds: (a) single dose of device, (b) multiple unit dose device and (c) multi-dose device.
For the inhaler of the first kind, single dose of metering loads in small container by manufacturer, and small container great majority are animal glue capsules.Capsule need utilize box separately or container to obtain, and it is inserted in the container of inhaler.Secondly, capsule must utilize pin or cutting blade open or bore a hole, to suck air-flow taking away powder by capsule, or utilizes centrifugal force when sucking to be disengaged in the hole of powder by capsule.After suction, capsulae vacuus must remove by inhaler.Usually, insert or remove capsule needs dismounting inhaler, this for some sufferer be difficulty and irritating.
With other shortcoming that hard capsule is used in inhalation of dust relevant be: (a) not easily prevents dampness in air, (b) after capsule is exposed to high humility, to open or perforation can be had any problem, break because it can cause or cave in, and (c) may suck capsule fragments.In addition, have report to mention, the eliminating of a lot of capsule not exclusively (such as, Nielsen etc., 1997).
Some capsule inhaler is provided with box, and independent capsule can receive in compartment by being wherein transferred to, and can implement perforation and emptying, in reception compartment as described in WO 92/03175.Other capsule inhaler has rotation box, rotates in box and has capsule compartment, with release medicine (as WO91/02558 and GB 2242134) on its axle that can be brought to air conduit.They comprise multiple unit dose inhalers with hood-shaped inhaler, and it supplies the unit dose of limited number of time on disk or band.
Hood-shaped inhaler has better moisture integrity than capsule inhaler to medicine.The thin slice of big envelope and cover is punched or taken off and can obtain powder by big envelope thin slice.When replacing disk with the band of cover, the number of medicament can be increased, but will blanking bar be replaced, can bring inconvenience for sufferer.Therefore, the medicament system of this device and merging is usually made to be finished and is namely lost, and it comprises the technology of transporting band and opening hood bag.
Many dose inhaler do not comprise the power formulations measured in advance.The medicament measuring construction that they contain larger container and need operate by sufferer.Container content has the medicament of many times, utilizes volume displacement a large amount of powder can be separated into unit dose separately.Existing various different pharmaceutical quantities geodesic structure, comprises rotatable thin film (e.g., EP0069715) or disk (e.g., GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinder (e.g., EP 0166294; GB 2165159 and WO 92/09322) and rotatable frustum (as, WO 92/00771), all all there is cavity, cavity can insert the powder from container, other multi-dose device have measure landslide (as, US 5201308 and WO 97/00703) or there is local or depression around in case by the powder of certain volume by container move on to conveying compartment or air conduit measurement piston (as, (Ex.EP 0505321, WO 92/04068 and WO 92/04928) or measure landslide, as (being called Novolizer SD2FL in the past), it is described in following patent: WO97/000703, WO03/000325, WO03/061742and WO2006/008027.
Reproducible medicament measurement is one of thing of the major concern of multiple medicines agent inhaler device.
That power formulations needs and stable flowing property, because when medicament measuring cup or medicament measurement cup aperture are inserted usually under the impact of gravity.
In order to again dose the inhaler of single medicament and multiple unit dose, maker need ensure the degree of accuracy that medicament measures and repeatability.On the other hand, multi-agent inhaler can contain more medicament, but its number of processes of filling up medicament is general lower.
Because the inhaling air stream in multi-dose device is usually directly crossed medicament and is measured lumen pore, and because the bulk of multi-agent inhaler and firm medicament measuring system cannot be sucked air-flow by this stirs, therefore agglomerates is only siphoned away by lumen pore simply, and hardly agglomerates is disperseed when disengaging.
Therefore, independent disassembling tool is needed.But in fact, they not always inhaler design a part.Because multi-dose device has the medicament of high number, its powder can be attached on the inwall of air conduit, and the device of dispersion caking must be minimized, and/or these parts of rule cleaning must be feasible, and medicament left in device can not be affected.The medicament reservoir that namely the useful mistake of some multi-agent inhalation apparatus loses, it can be replaced (as WO 97/000703) after the medicament implementing pre-determined number.For this, there are the semi-permanent many times of dose inhaler using the medicament reservoir namely lost, even more harsh to preventing the demand of drug accumulation.
Except using except dry powder inhaler, the present composition also can be taken in fog, and its operation via promotion gas or can utilize so-called nebulizer, and on materia medica, the solution of active substance is through high-pressure injection, and produce can the fog of Inhaled Particles After Acute.The advantage of these nebulizers is that its propelling gas can be fully allocated.
This nebulizer is described in as PCT patent application No.W0 91/14468, international monopoly No.WO 97/12687, and description of the present invention has with reference to content wherein.
Can be aqueous solution or water slurry for sucking the spray composite delivering to pulmonary, can be maybe the fog carried by the press packet of the dose inhaler of picture metering, it utilizes the propulsive gas of suitable liquefaction.The fog composition being applicable to sucking can be suspension or solution, and it is generally containing active ingredient and suitable propulsive gas, and propulsive gas comprises picture fluorocarbon or hydrogeneous chlorofluorocarbons or its mixture.Particularly hydrofluoroalkane, such as dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, especially HFA 134a, 1,1,1,2,3,3,3-seven fluoro-n-propane or its mixture.Carbon dioxide or other suitable gas also can be used as propulsive gas.
Fog composition can not tool adjuvant, or optionally containing the other formulation auxiliaries known by those skilled in the art, such as, surfactant such as oleic acid or lecithin and cosolvent, such as ethanol.Pressure formula is generally placed in tank (such as aluminium pot), and utilizes valve (such as metering valve) come airtight and be provided with the starter started by mouth.
Suck the medicine taken and have a controlled granular size.The best granular size normally 1-10 μ of inspiration bronchi, preferably 2-5 μ.The granule with 20 μ sizes seems too large when being drawn into small airway.Traditional method such as micronization can be utilized, can the granular size of active ingredient is reduced to desired.Utilize air classification or screening, separable go out the part of wanted size.Preferably, granule will be signed an undertaking crystalloid.
Utilize the medicament repeatability that micronized powder not easily reaches high, because the bad and easy conglomerate of their mobility.In order to improve the efficiency of dry powder composition, granule should have larger granularity in inhaler, and will diminish when discharging into respiratory tract.Therefore general is as the adjuvant of lactose or glucose.The granular size of adjuvant is generally much larger than Sucked medicine of the present invention.When adjuvant is lactose, it is generally ground lactose, preferably the mono-water and milk sugar of crystalloid α.
Pressure fog compositions is generally contained in the tank of valve, particularly metering valve.Tank optionally scribbles the skin of plastics, such as chlorine carbide polymer, as described in W096/32150 patent.Tank is provided with the starter of applicable mouth conveying.
The compositions being generally used for nose conveying comprises the compositions of forenamed suction, and separately comprise non-pressurised solution or the compositions of suspension, it is in the inert carrier of such as water, it is optionally containing traditional adjuvant, as buffer agent, antimicrobial, sense dressing agent and stickiness dressing agent etc., it can be taken by nose.
The formula of general skin and lagging comprises traditional watery or non-aqueous vehicles, the unguentum of such as oils and fats, ointment, varnish or slurry or dusting powder drug, paster or film.
Preferably, compositions has the form of unit dose, as the aerosol medicament of tablet, capsule or metering, makes sufferer can take single medicament.
Constituent parts medicament contains between compound 0.5 μ g to 500 μ g of the present invention, preferably, between 5 μ g to 100 μ g.
The dosage obtaining each active ingredient needed for curative effect is certainly decided by specific active ingredient, takes mode, sufferer object and the factor such as the imbalance that will treat or disease.
Active ingredient need take 1 to 6 times in one day, is enough to reach desired activity.Preferably, active ingredient is taken once or secondary for one day.
The suitable PDE4 inhibitor combined with the compounds of this invention has benafentrine maleic acid, according to the acid of its azoles, denbufylline, rolipram, Cipamfylline, zardaverine, arofylline, filaminast, Tai Lusite, appropriate Fei Site, Piclamilast, tolafentrine, the loose Pulan of rice, drotaverine, hydrochloride, Li meter Si Te, roflumilast, cilomilast, oglemilast, apremilast, Tetomilast, filaminast, (R)-(+)-4-[2-(3-cyclopentyloxy-4-anisyl)-2-phenethyl] pyridine (CDP-840), N-(3, the chloro-4-pyridine radicals of 5-bis-)-2-[1-(4-fluorophenyl)-5-hydroxyl-1H-indol-3-yl]-2-acetamide oxide (GSK-842470), 9-(2-fluorophenyl)-N6-methyl-2-(trifluoromethyl) adenine (NCS-613), N-(the chloro-4-pyridine radicals of 3,5-bis-)-8-methoxy quinoline-5-Methanamide (D-4418), 3-[3-(cyclopentyloxy)-4-anisyl]-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride (V-11294A), 6-[3-(N, N-dimethyl-carbamyl) benzenesulfonyl]-4-(3-anisidino-)-8-methylquinoline-3-Methanamide hydrochloride (GSK-256066), 4-[6,7-diethoxy-2,3-bis-(methylol)-naphthalene-1-base l]-1-(2-methoxyethyl) pyridine-2 (1H)-one (T-440), (-)-trans-2-[3'-[3-(N-cyclopropyl carbamyl)-4-oxygen-Isosorbide-5-Nitrae-dihydro-1,8-naphthyridines-1-base]-3-fluorine diphenyl-4-base]-cyclopropane-carboxylic acid (MK-0873), CDC-801, UK-500001, BLX-914, 2-carbomethoxy-4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy-phenyl)-cyclohexyl-1-ketone, along [4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl)-cyclohexane extraction-1-alcohol, CDC-801, 5 (S)-[3-(cyclopentyloxy)-4-anisyl]-3 (S)-(3-methyl toluene base) piperidines-2-ketone (IPL-455903), ONO-6126 (Eur Respir J 2003,22 (Suppl.45): Abst 2557) and PCT patent WO03/097613, WO2004/058729, WO 2005/049581, the salt of the patent applications such as WO 2005/123693 and WO 2005/123692.
Prednisolone is comprised with the suitable corticosteroid of compound combination of the present invention and glucocorticoid, methyl meticortelone, dexamethasone, dexamethasone Sai Pasailete (dexamethasone cipecilate), Nai Feikete, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, corticoid, omcilon acetonide, fluocinolone acetonide acetic acid compound, fluocinonide, clocortolone pivalate, first Bo Nisonglong vinegar propyl ester, dexamethasone palmitate, tipredane, corticoid vinegar propyl ester, prednicarbate, alclometasone depropionate, halometasone, methylprednisolone suleptanate, its loose furoate not beautiful, rimexolone, prednisolone method ester, ciclesonide, butixocort propionate, RPR-106541, deprodone propionate, FLUTICASONE PROPIONATE, fluticasone furoate, halogen Beta pine dipropionate, loteprednol etabonate, Beta rice pine butyrate propionic ester, flunisolide, prednisone, dexamethasone na phosphates, omcilon, beta rice pine 17-valerate, beta rice pine, beta rice pine dipropionate, 21-chloro-11 betas-hydroxyl-17 A Erfa-[2-methylsulfonyl] acetoxyl group]-4-pregnene-3,20-diketone, De Xisuo butyryl ciclesonide, tixocortol acetate, tixocortol sodium succinate, NS-126, Bo Nisonglong na phosphates and fourth third hydrocortisone, Bo Nisonglong sodium inclined sulphur toluene hydrochlorate, and clobetasol propionate.
The particularly preferred pharmaceutical composition of the present invention comprises the compound of formula (I) and one or more additives for the treatment of effective dose, and this additive is selected from the compound in mometasone, furoate, ciclesonide, budesonide, fluticasone propionate, fluticasone furoate, rolipram, roflumilast, cilomilast and PCT patent application WO03/097613, WO2004/058729, WO 2005/049581, WO 2005/123693 and WO 2005/123692.
The particularly preferred pharmaceutical composition of the present invention comprises the compound of formula (I) and one or more additives for the treatment of effective dose, and this additive is selected from momestasone furoate, ciclesonide, budesonide, fluticasone propionate, fluticasone furoate, rolipram, roflumilast and cilomilast etc.
Therefore, in one aspect of the invention, compositions comprises compound and the hydrocortisone of formula (I).Particularly preferred hydrocortisone is selected from momestasone furoate, ciclesonide, budesonide, fluticasone furoate and fluticasone propionate etc.
In another aspect of this invention, compositions comprises compound and the PDE4 inhibitor of formula (I).Particularly preferred PDE4 inhibitor is selected from the compound of rolipram, roflumilast, cilomilast and PCT patent application WO03/097613, WO2004/058729, WO 2005/049581, WO 2005/123693 and WO 2005/123692, compositions separately comprises hydrocortisone, and it is selected from momestasone furoate, ciclesonide, budesonide, fluticasone furoate and fluticasone propionate.
In another preferred implementation of the present invention, compositions comprises the compound of formula (I) and the momestasone furoate of the upper effective dose for the treatment of.Optionally, compositions also comprises PDE4 inhibitor.
Compositions of the present invention can be used to treat respiratory disorder, and wherein, the use of bronchodilator is of value to asthma, acute or chronic bronchitis, emphysema or chronic obstructive pulmonary disease (COPD) etc.
Reactive compound can be taken together with PDE4 inhibitor, corticosteroid or glucocorticoid in same medicine, or in different components alone, simultaneously, adjoint or sequentially take in identical or different mode.
Also can consider, all activating agents are close proximity taken at one time or on the time.Or, in the morning or other more late time take one or two kinds of active ingredients.Or within one day, secondary takes one or two kinds of active ingredients, and takes other active ingredient once a day, its also can one of one day secondary ground simultaneously, or to take respectively.
Preferably, the same time takes at least two kinds of active ingredients, and more preferably, the same time takes all active ingredients.Preferably, at least two kinds of active ingredients are taken with mixture, and more preferably, all active ingredients are taken with mixture.
Active compound composition of the present invention is taken, and preferably utilizes inhaler, and particularly dry powder inhaler sucks and takes.But, can also other any form or non-for oral administration or oral taking.Herein, composition for inhalation is preferably type of service, especially to the treatment of obstructive pulmonary disease or asthma.
The carrier suitable in addition of active compound formulations of the present invention can find in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2000.Following non-limiting example shows the representational pharmaceutical composition of the present invention.
Formula example
Formulation Example 1 (oral suspension agent)
Composition Amount
Reactive compound 3mg
Citric acid 0.5g
Sodium chloride 2.0g
Essence of Niobe antiseptic 0.1g
Granular sugar 25g
Sorbitol (70% solution) 11g
Aluminium-magnesium silicate 1.0g
Flavouring agent 0.02g
Stain 0.5mg
Distilled water To the surplus of 100mL
Formulation Example 2 (hard-gelatin capsules for oral use)
Composition Amount
Reactive compound 1mg
Lactose 150mg
Magnesium stearate 3mg
Formulation Example 3 (suction Jiao Kebao)
Composition Amount
Reactive compound (micronization) 0.2mg
Lactose 25mg
Formulation Example 4 (there is DPI suction formula)
Composition Amount
Reactive compound (micronization) 15mg
Lactose 3000mg
Formulation Example 5 (MDI formula)
Composition Amount
Reactive compound (micronization) 10g
The fluoro-n-propane of 1,1,1,2,3,3,3-seven To the surplus of 200ml

Claims (20)

1. the compound of a formula (I) or its pharmaceutically acceptable salt:
Wherein:
● X becomes Ji Tuan – CH=CH-or-CH together with Y shape 2-O-, wherein, at-CH 2when-O-, methylene is connected to the carbon atom had in the amino-substituent of X, and oxygen atom is connected to the carbon atom had in the phenyl ring of Y,
● R 1and R 2represent hydrogen atom or C independently 1-4alkyl,
● R 3expression
Group,
Wherein:
Zero R arepresent hydroxyl,
Zero R band R crepresent thienyl, phenyl or cyclopenta independently,
Zero * represents R 3be connected to the junction point of the remainder of the molecule of formula (I),
● A 1with A 2represent C independently 1-6alkylidene,
● L represents direct key ,-O-,-NH (CO)-Huo – NH (CO) O-group, and Qi Zhong is when – NH (CO) O-, and nitrogen-atoms is connected to W substituent group and oxygen atom is connected to A2 substituent group; And
● W represents direct key or phenylene, and described phenylene is optionally selected from halogen atom, C by one or more 1-4the substituent group of alkoxyl and cyano group replaces.
2. compound according to claim 1, wherein, X is together with Y shape Cheng – CH=CH-.
3. compound according to claim 1 and 2, wherein, R 1and R 2represent hydrogen atom or methyl independently.
4. compound according to claim 3, wherein, R 1and R 2the two is all hydrogen atoms.
5. compound according to claim 1 and 2, wherein, R 1represent hydrogen atom, R 2represent methyl.
6. compound according to claim 1, wherein, R 3expression i) group, wherein:
● R arepresent hydroxyl,
● R band R cthe two is all thienyls.
7. compound according to claim 1, wherein, L Biao Shi – O-Huo – NH (CO)-group.
8. compound according to claim 1, wherein, W represents phenylene, and it is optionally replaced by one or two substituent group being selected from chlorine atom, methoxyl group and cyano group.
9. compound according to claim 8, wherein, described phenylene is replaced by the substituent group that two are selected from chlorine atom, methoxyl group and cyano group.
10. compound according to claim 1, wherein
● X is together with Y shape Cheng – CH=CH-Huo – CH 2-O-group,
● R 1represent hydrogen atom or methyl,
● R 2represent hydrogen atom or methyl,
● R 3the group of expression (i), wherein R arepresent hydroxyl, R band R cindependently selected from phenyl, cyclopenta and thienyl,
● A 1and A 2represent C independently 1-6alkylidene,
● L is selected from direct Jian, – O-, – NH (CO)-He – NH (CO) O-group, and
● W represents direct key or phenylene, and this phenylene is optionally replaced by one or two substituent group being selected from chlorine atom, fluorine atom, methoxyl group and cyano group.
11. compounds according to claim 10, wherein
● X together with Y shape Cheng – CH=CH-,
● R 1represent hydrogen atom,
● R 2represent hydrogen atom or methyl,
● R 3the group of expression (i), wherein, R arepresent hydroxyl, R band R cthe two is all thienyls,
● A 1and A 2represent C independently 1-6alkylidene,
● L is selected from direct Jian, – O-, – NH (CO)-He – NH (CO) O-group, and
● W represents direct key or phenylene, and this phenylene is optionally replaced by one or two substituent group being selected from chlorine atom, methoxyl group and cyano group.
12. compounds according to claim 11, wherein, R 2represent hydrogen atom, L Xuan Zi – O-, – NH (CO)-He – NH (CO) O-group, W represents the phenylene replaced by the substituent group that two are selected from chlorine atom, methoxyl group and cyano group.
13. compounds according to claim 12, wherein, R 2represent methyl, L Xuan Zi – O-, – NH (CO)-He – NH (CO) O-group, W represents the phenylene replaced by the substituent group that two are selected from chlorine atom, methoxyl group and cyano group.
14. compounds according to claim 1, it is one of following material:
Trans-4-[(9-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } nonyl) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate two formate;
Trans-4-[2-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl) phenoxy group] ethyl } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)) acetate list formate;
Trans-4-[3-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl) phenoxy group] propyl group } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate list formate;
Trans-4-[2-[(6-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } hexyl) oxygen base] ethyl } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate list hydrofluoride;
Trans-4-[3-[(6-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } hexyl) oxygen base] propyl group } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)-acetate list hydrofluoride;
Trans-4-[{ 3-[4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenoxy group] propyl group } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate list formate;
Trans-4-[2-[4-([(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl]-amino methyl) phenoxy group] propyl group (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)-acetate list hydrofluoride;
Trans-4-[3-[4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenoxy group] ethyl } (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls)-acetate list hydrofluoride;
Trans-4-((3-(2-chloro-4-(((2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl)-5-anisidino-)-3-oxygen propyl group) (methyl) is amino)-cyclohexyl hydroxyl (two-2-thienyls) acetate list hydrofluoride;
Trans-4-((3-(2-chloro-4-(((2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl) phenyl amino)-3-oxygen propyl group) (methyl) is amino) cyclohexyl hydroxyl-(two-2-thienyls) acetate list hydrofluoride;
Trans-4-[{ 3-[2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxy phenoxy] propyl group } (methyl) is amino] cyclohexyl hydroxyl-(two-2-thienyls) acetate list hydrofluoride;
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl) oxygen base] ethyl }-(methyl) is amino] cyclohexyl hydroxyl-(two-2-thienyls) acetate list hydrofluoride;
Trans-4-[(3-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino }-3-oxygen propyl group) (methyl) amino]-1-cyclohexyl hydroxyl-(two-2-thienyls) acetate;
Trans-4-[(3-{ [4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] is amino }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate dihydrofluoride;
Trans-4-[(4-{ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxycarbonyl propyl] is amino }-4-oxygen-butyl) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate;
Trans-4-[(3-{ [fluorine-based-4-of 2-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino }-3-oxygen propyl group) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate;
Trans-4-[(3-{ [4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-3-anisyl] is amino }-3-oxygen propyl group) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate dihydrofluoride;
Trans-4-[(3-{ [2, the fluoro-4-of 5-bis-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] amino-3-oxygen propyl group) (methyl) amino]-cyclohexyl hydroxyl (two-2-thienyls) acetate dihydrofluoride;
Trans-4-[(3-{ [fluorine-based-4-of 2-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-d dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] is amino }-3-oxygen propyl group) (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate dihydrofluoride;
Trans-4-[(3-{ [2-chloro-4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl)-5-anisyl] amino-3-oxygen propyl group)-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate dihydrofluoride;
Trans-4-[3-[2-chloro-4-(2-{ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } ethyl)-5-methoxy phenoxy] propyl group } (methyl)-amino] cyclohexyl hydroxyl (two-2-thienyls) acetate dihydrofluoride;
Trans-4-[{ 2-[({ [2-cyano group-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl)-oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate dihydrofluoride;
Trans-4-[{ 2-[({ [2, the fluoro-4-of 5-bis-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl) phenyl] amino carbonyl) oxygen base] ethyl-(methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate dihydrofluoride;
Trans-4-[{ 4-[2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-methoxy phenoxy] butyl } (methyl) is amino] cyclohexyl hydroxyl (two-2-thienyls) acetate dihydrofluoride;
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(5-hydroxyl-3-oxo-3,4-dihydro base-2H-1,4-benzoxazine-8-base) ethyl] amino methyl)-5-anisyl] amino carbonyl) oxygen]-ethyl (methyl) amino] cyclohexyl hydroxyl (two-2-thienyls) acetate;
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl) oxygen] ethyl } (methyl)-amino] cyclohexyl (2R)-cyclopenta (hydroxyl) phenyl acetate; And
Trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] amino methyl)-5-anisyl] amino carbonyl) oxygen base] ethyl (methyl) amino] cyclohexyl (2S)-cyclopenta (hydroxyl) 2-thiophene acetate
Or its pharmaceutically acceptable salt.
15. compounds according to claim 14, it is trans-4-((3-(2-chloro-4-(((2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethylamino) methyl)-5-anisidino-)-3-oxygen propyl group) (methyl) is amino)-cyclohexyl hydroxyl (two-2-thienyls) acetate list hydrofluoride; Or its pharmaceutically acceptable salt.
16. compounds according to claim 14, it is trans-4-[{ 2-[({ [2-chloro-4-({ [(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1,2-dihydroquinoline-5-base) ethyl] is amino } methyl)-5-anisyl] is amino } carbonyl) oxygen base] ethyl } (methyl) is amino] cyclohexyl hydroxyl-(two-2-thienyls) acetate list hydrofluoride; Or its pharmaceutically acceptable salt.
17. 1 kinds of pharmaceutical compositions, it comprises the compound and pharmaceutically acceptable diluent or carrier that limit any one of claim 1 to 16.
The compound limited any one of 18. claim 1 to 16 is used for the treatment of in manufacture the purposes be selected from pulmonary disease, premature labor, glaucoma, neurological disorder, inflammation and the pathologic conditions of gastroenteropathy or the medicine of disease.
19. purposes according to claim 18, wherein said pathologic conditions or disease are asthma or chronic obstructive pulmonary disease.
20. 1 kinds of combination products, it comprises the compound that (i) compound according to any one of claim 1 to 16 and (ii) another kind are selected from corticosteroid and PDE4 inhibitor.
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